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Cold Exposure & Other Mild Stressors for Increased Health & Longevity

Cold Exposure Exercise Fasting UCPs UCP1 UCP3 FGF21

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#201 Dean Pomerleau

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Posted 13 April 2016 - 01:49 PM

Gordo wrote:

Brown Adipose Tissue Is Linked To A Distinct Thermoregulatory Response To Mild Cold In People

(Full/Preliminary article is downloadable from above, this is very recent work)

 

Great find Gordo! Very interesting study [1]. It is part of a clinical trial to study BAT in humans, and particularly its potential to combat insulin resistance and obesity. Here is the table from the full text of the study showing the characteristics of the BAT+ and BAT- subjects:

 

qb2vLOB.png

 

The only significant difference between groups was age - with the BAT+ group being almost 20 years younger on average than the BAT- group! Us oldsters are really at a disadvantage when it comes to BAT. The entire subject pool was pretty hefty, verging on obese, but the BAT+ group had a tendency to be a bit leaner.

 

As you observed, the BAT+ group was able to maintain their core body temperature during CE, while the BAT- folks saw a drop in core temperature despite being slightly less cold-challenged than the BAT+ group (the ambient temperature was adjusted for each subject to be just above their individual shivering threshold and the BAT+ group had a lower ambient temperature threshold). This again shows that it may not be possible for cold-acclimated humans to increase core temperature in response to cold like is observed in rodents, but instead to simply to maintain it.

 

It continues to amaze me how little BAT even BAT+ folks have - 67ml on average. That's only a little over 2oz. That's tiny. It's hard to believe so little tissue can be responsible for so much thermogenesis, and it makes me wonder whether BAT is working in concert with other thermogenic processes (sarcolipin-induced futile cycling in muscle sarcoplasmic reticulum perhaps?) in the BAT+ group to maintain body temperature during a cold challenge. Having measureable BAT may therefore be a marker for cold adaptation and/or genetic variations that heighten thermogenic capacity.

 

I hope these researchers publish a lot more detailed investigation of the metabolism and blood measures in these subjects, per their promise in the clinical trial description. 

 

Gordo wrote:

They found that supraclavicular skin/surface temperature measurements were a good method of measuring BAT activity.  The last such measurement I took on myself after CE showed 96.0F.  

 

Can you remind me how you measure your skin temperature? I might be interested in doing the same, so we could compare notes.

 

Thanks!

 

--Dean

 

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

[1] Front. Physiol. | doi: 10.3389/fphys.2016.00129

 

Brown Adipose Tissue Is Linked To A Distinct Thermoregulatory Response To Mild Cold In People
 
 Maria Chondronikola1*, Elena Volpi1,  Elisabet Borsheim1, Tony Chao1,  Craig Porter1, Palam Annamalai1, Christina Yfanti1,  Sebastien M. Labbe2,  Nicholas M. Hurren1, Ioannis Malagaris1, Fernardo Cesani1 and  Labros S. Sidossis1
1University of Texas Medical Branch, USA
 
Brown adipose tissue (BAT) plays an important role in thermoregulation in rodents. Its role in temperature homeostasis in people is less studied. To this end, we recruited 18 men [8 individuals with no/minimal BAT activity (BAT-) and 10 with pronounced BAT activity (BAT+)]. Each volunteer participated in a 6 h, individualized, non-shivering cold exposure protocol. BAT was quantified using positron emission tomography/computed tomography. Body core and skin temperatures were measured using a telemetric pill and wireless thermistors, respectively. Core body temperature decreased during cold exposure in the BAT- group only (-0.34oC, 95% CI: -0.6 to -0.1, p = 0.03), while the cold-induced change in core temperature was significantly different between BAT+ and BAT- individuals (BAT+ vs. BAT-, 0.43oC, 95% CI: 0.20 to 0.65, p = 0.0014). BAT volume was associated with the cold-induced change in core temperature (p = 0.01) even after adjustment for age and adiposity. Compared to the BAT- group, BAT+ individuals tolerated a lower ambient temperature (BAT-: 20.6± 0.3oC vs. BAT+: 19.8 ± 0.3oC, p=0.035) without shivering. The cold-induced change in core temperature (r = 0.79, p = 0.001) and supraclavicular temperature (r = 0.58, p = 0.014) correlated with BAT volume, suggesting that these non-invasive measures can be potentially used as surrogate markers of BAT when other methods to detect BAT are not available or their use is not warranted. These results demonstrate a physiologically significant role for BAT in thermoregulation in people. This trial has been registered with Clinaltrials.gov: NCT01791114 https://clinicaltria...ow/NCT01791114)

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#202 Dean Pomerleau

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Posted 13 April 2016 - 02:57 PM

Cold Exposure Upregulates Heat Shock Proteins

 

On a tangent, I was thinking about heat shock proteins. Those are released by all sorts of stress, including CE. But they got their name originally from heat stress. In this context, I wonder about saunas as a hormetic generator of HSP. Saunas are popular in Northern Europe, Russia etc. as a sort of folk "health therapy", though I suppose that is not meaningful in and of itself. A sauna seems about 180 degrees from CE. An interesting wrinkle is that in some of those cultures they like to combine both - first you cook in a sauna, then you plunge into ice cold water or snow - and in Russia, I think they even whip each other with nettle twigs/switches. I bet these various methods all generate HSP, though what the net effect is I have no idea.

 

Tom,

 

More good questions. For those not familiar with Heat Shock Proteins (HSPs) they are a family of proteins the body produces in response to various stressful conditions, not just thermal extremes. Their primary role appears to be to act as a chaperone to prevent misfolding and aggregation of other proteins under stressful conditions. They also appear to serve as signalling molecules for cellular stress, that kick in a host of other  biochemical responses, including beneficial chances to the cardiovascular and immune systems. Both acute and chronic cold exposure trigger the induction of a variety of HSPs as a result of elevated norepinephrine [1].

 

Here is the section from the Cold Exposure Albatross post discussing heat shock proteins (follow link for references):

 

Improved Heat Tolerance / Increased Heat Shock Protein Expression - While it's not clear heat shock proteins (HSPs) increase lifespan in mammals like they do in lower organisms (like C elegans), HSPs are definitely important for stress resistance [18], and in particularly for the ability to cope with heat stress, hence the name. CR preserves HSP induction in response to thermal stress in aging mice [20], and prevent the age-related decline in several heat shock protein [21], and especially HSP70 [19] and HSP90 [21].  So might the cold of CE reduce one's heat shock protein levels, and ruin one's ability to cope with high temperatures? Nope. Quite the opposite in fact. 
 
Study [13] found that the induction of three important heat shock proteins, Hsp70, Hsp90 and Hsp110 was higher in tissues of mice housed at 22 °C than mice housed at thermoneutrality (30°C) following 6 h of heat stress (i.e. high temperatures) which elevated core body temperature to 39.5 °C. So it looks like relative to living at comfortable, thermoneutral temperatures, CE helps with thermal tolerance at both extremes - hot and cold, by improving heat shock protein induction. Interestingly, [14] found increased expression of one of Hsp70 is associated with improved insulin sensitivity in monkeys and humans - "higher levels of [...] HSP70 protect against insulin resistance development during healthy aging." Review article [16] is a good discussion of heat shock proteins and lifespan in general, and [17] is a study that shows genetic mutations in heat shock proteins may be associated with improved human survival.
 
Here is a recent study [2] that  I overlooked in the Albatross post, which found people stationed in Antarctica over the winter and subject to cold had higher circulating HSP65 (the only HSP they tested for) than a control group stationed in tropical India over the same period.
 
In summary, both acute and chronic cold exposure upregulates HSPs in all organisms tested, from flies to rodents to humans. Yet one more benefit of cold. As to your question about the potential benefits (or harm) of rapid thermal cycling (e.g. a plunge into cold water after a sauna), I haven't come across evidence pointing one way or the other.
 
--Dean
 
------------
[1] Am J Physiol. 1995 Jul;269(1 Pt 2):R38-47.
 
Characterization and regulation of cold-induced heat shock protein expression in 
mouse brown adipose tissue.
 
Matz JM(1), Blake MJ, Tatelman HM, Lavoi KP, Holbrook NJ.
 
Author information: 
(1)Department of Pharmacology and Toxicology, University of North Dakota, Grand
Forks 58202, USA.
 
The accumulation of heat shock proteins (HSPs) after the exposure of cells or
organisms to elevated temperatures is well established. It is also known that a
variety of other environmental and cellular metabolic stressors can induce HSP
synthesis. However, few studies have investigated the effect of cold temperature 
on HSP expression. Here we report that exposure of Institute of Cancer Research
(ICR) mice to cold ambient temperatures results in a tissue-selective induction
of HSPs in brown adipose tissue (BAT) coincident with the induction of
mitochondrial uncoupling protein synthesis. Cold-induced HSP expression is
associated with enhanced binding of heat shock transcription factors to DNA,
similar to that which occurs after exposure of cells or tissues to heat and other
metabolic stresses. Adrenergic receptor antagonists were found to block
cold-induced HSP70 expression in BAT, whereas adrenergic agonists induced BAT HSP
expression in the absence of cold exposure. These findings suggest that
norepinephrine, released in response to cold exposure, induces HSP expression in 
BAT. Norepinephrine appears to initiate transcription of HSP genes after binding 
to BAT adrenergic receptors through, as yet, undetermined signal transduction
pathways. Thermogenesis results from an increase in activity and synthesis of
several metabolic enzymes in BAT of animals exposed to cold challenge. The
concomitant increase in HSPs may function to facilitate the translocation and
activity of the enzymes involved in this process.
 
PMID: 7631901
 
-------------
[2] International Journal of Scientific and Research Publications, Volume 4, Issue 5, May 2014 1
ISSN 2250-3153
 
Heat Shock Protein Response to Chronic Cold Exposure in Antarctic Expedition Members
 
IB Udaya*
, CC Laxmi**
, AK Kavitha†
, TN Satyaprabha††
, TR Raju#
, Shripad Patil ##
 
 
 Abstract- The heat shock response is seen when cells are
exposed to extremes of thermal environment, which may be
acute or chronic. The heat shock response is featured by
increased expression of heat shock proteins (HSPs). One such
key stresses is extreme cold environment as seen in Antarctica.
The Antarctic continent on the planet Earth is full of
environmental challenges. It is considered as natural stress
model. The objective of this study was to study the effect of
chronic cold environment on HSP levels. Seventeen healthy men
of XXVI Indian Antarctic expedition with mean age of
39.7±1.95 years and age ranged from 29 to 56 years participated
in this study. Antibodies of IgG, IgA and IgM classes against
HSP65 were investigated by indirect ELISA method. Samples
were collected in 2 phases. In phase-1, pre-expedition samples
were collected before leaving to Antarctica at National Center for
Antarctic and ocean research (NCAOR), Goa. In phase-2, end
expedition samples were collected after 11 months of stay in
Antarctica in an Indian permanent station (Maitri) during polar
days. The raw data on analysis using statistical tool revealed that
the anti-HSP65 IgM antibody were significantly elevated (p=
<0.001). It was observed that the anti-HSP65 antibodies were
increased in expedition members compared with the control
group who stayed in India. The present study concluded that HSP
expression increased in Indian Antarctic expedition members
who were exposed to chronic cold stress in Antarctica.
 
 Index Terms- HSP65, Chronic cold stress, Antarctica, Immunological response.

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#203 Gordo

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Posted 13 April 2016 - 03:12 PM

I hope these researchers publish a lot more detailed investigation of the metabolism and blood measures in these subjects, per their promise in the clinical trial description. 

 

I don't really like how they conducted this experiment, but you may find some more info related to the above in this other study that was just published:

A randomized trial of cold-exposure on energy expenditure and supraclavicular brown adipose tissue volume in humans

The nice thing about this one is that they did CE for 6 weeks (62.5 degrees F exposure for 2 hours a day).

If I'm reading it right, they found that level of CE resulted in burning about an extra 100 calories a day.
They also found that BAT volume increased by 23% in 6 weeks with this level of CE.

 

Can you remind me how you measure your skin temperature? I might be interested in doing the same, so we could compare notes.

 

Not sure how "legit" this is, but I took a standard digital oral thermometer, firmly pushed it into the supraclavicular:

picture_51330723976374.png

 

so that the probe end was completely enveloped in skin (I leaned my head and neck over until it was covered).


Edited by Gordo, 13 April 2016 - 04:47 PM.


#204 Dean Pomerleau

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Posted 13 April 2016 - 04:04 PM

Thanks Gordo,

 

I was considering purchasing a couple of these iButtons, along with the interface to download the data. This is the same hardware used to continuously monitor and log skin temperature in the study we're discussing (doi:10.3389/fphys.2016.00129), as well as several other human BAT studies (e.g. PMIDs 24922545 and 23867626). This study [1] is an evaluation of iButtons for human skin temperature monitoring. Here is what they look like taped to the skin around the supraclavicle region:

 

In-the-clavicular-and-sternal-region-iBu

 

At $29 a pop (plus $100 for the interface kit), I'm not going to spring for as many as shown in the photo! But if you and/or anyone else would agree to purchase them as well for comparison (competition ), I'd be game...

 

--Dean

 

----------

[1] Physiol Behav. 2006 Jul 30;88(4-5):489-97. Epub 2006 Jun 23.

 
Evaluation of wireless determination of skin temperature using iButtons.
 
van Marken Lichtenbelt WD(1), Daanen HA, Wouters L, Fronczek R, Raymann RJ,
Severens NM, Van Someren EJ.
 
Author information: 
(1)Nutrition and Toxicology Institute Maastricht (NUTRIM), Department of Human
Biology, Maastricht University, Maastricht, The Netherlands.
markenlichtenbelt@hb.unimmaas.nl
 
Measurements of skin temperatures are often complicated because of the use of
wired sensors. This is so in field studies, but also holds for many laboratory
conditions. This article describes a wireless temperature system for human skin
temperature measurements, i.e. the Thermochron iButton DS1291H. The study deals
with validation of the iButton and its application on the human skin, and
describes clinical and field measurements. The validation study shows that
iButtons have a mean accuracy of -0.09 degrees C (-0.4 degrees C at most) with a 
precision of 0.05 degrees C (0.09 degrees C at most). These properties can be
improved by using calibration. Due to the size of the device the response time is
longer than that of conventional sensors, with a tau in water of 19 s. On the
human skin under transient conditions the response time is significantly longer, 
revealing momentary deviations with a magnitude of 1 degrees C. The use of
iButtons has been described in studies on circadian rhythms, sleep and cardiac
surgery. With respect to circadian rhythm and sleep research, skin temperature
assessment by iButtons is of significant value in laboratory, clinical and home
situations. We demonstrate that differences in laboratory and field measurements 
add to our understanding of thermophysiology under natural living conditions. The
advantage of iButtons in surgery research is that they are easy to sterilize and 
wireless so that they do not hinder the surgical procedure. In conclusion, the
application of iButtons is advantageous for measuring skin temperatures in those 
situations in which wired instruments are unpractical and fast responses are not 
required.
 
PMID: 16797616

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#205 Gordo

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Posted 13 April 2016 - 05:09 PM

I love the idea of the temperature loggers, I was looking at the same one earlier, there are a few listings on eBay but they are missing the interface/data reader part which kind of makes them worthless to me.  There are several do-it-yourself instructions on the web to build something similar.  You can buy the iButton temp sensor part alone for under $2 but obviously you need more than just that...



#206 Dean Pomerleau

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Posted 13 April 2016 - 06:07 PM

Gordo,

 

If you can find an alternative temperature logging technology, let me know. Otherwise, I'm game for purchasing iButtons, if anyone else will too...

 

--Dean


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#207 Gordo

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Posted 14 April 2016 - 09:34 PM

Gordo,

 

If you can find an alternative temperature logging technology, let me know. Otherwise, I'm game for purchasing iButtons, if anyone else will too...

 

--Dean

I wonder if this one could be made to work?  It has the same detection range and resolution as the iButton, but much better tech since it logs via bluetooth and you don't need to buy an interface for it. Only $30 to find out... if it doesn't work, maybe I'll just use it to track indoor or outdoor temps.



#208 Dean Pomerleau

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Posted 15 April 2016 - 02:44 AM

Gordo,

That SensorBug looks pretty cool, and the price is better, since you don't in theory need a separate interface other than a Bluetooth 4.0 phone.

But it doesn't look like you can record the data, or even get the instantaneous temp data off the device except simply to view it in their App. It seems to me that what we want to do is have (at least) two temperature sensors at two different points on our body (e.g. one over BAT and one elsewhere) to see if the difference between them changes when BAT kicks in due to CE. With two (or more) sensors you can filter out changes due to ambient temperature, and see if the area over BAT is indeed differentially warmer compared to other parts of our body surface in response to cold.

I'm not sure that would be possible with the SensorBug at least without a lot of hacking.

What do you have in mind for usage of the device?

--Dean
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#209 Dean Pomerleau

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Posted 15 April 2016 - 03:14 PM

Beige is the New Brown - Implications for CR and Cold Exposure

 

All,

 

This is another one of those slightly complicated stories based on a new study [1] and related evidence. But I think it will be worth it to follow along for anyone practicing CR, either without or without CE. So I urge you to bear with me.

 

Rapamycin extends lifespan in mice [5], and was once considered a promising anti-aging therapy, possibly acting as a CR-mimetic. Like one of the effects of CR, rapamycin inhibits the anabolic protein complex called 'mTOR'. In fact, the 'R' in 'mTOR' stands for 'Rapamycin', as in "mammalian Target Of Rapamycin" (mTOR).

 

But a Michael points out here, Rapamycin has some nasty side effects. One of the biggies is by turning off mTOR, rapamycin results in immune system suppression as shown in the diagram below. Rapamycin is much worse in this regard than the immunosuppressive effects of CR that operates at least in part by the same mechanism, i.e. downregulation of mTOR by reducing circulating insulin and IGF-1. In fact rapamycin is used as an immunosuppressant drug given to organ transplant recipients to prevent organ rejection by turning down the vigilance of the immune system.

 

S1BX53m.png

 

That side-effect alone is enough reason to avoid taking rapamycin, unless you're an organ transplant recipient. Unfortunately for transplantees, immunosuppression isn't the only adverse side effect of rapamycin. It also reduces insulin sensitivity and impairs both glucose and lipid metabolism, leading to hyperlipidemia, metabolic syndrome and diabetes. But apparently the mechanism that causes these additional negative consequences of rapamycin has not been well understood...

 

This new study [1] sheds some light on that mystery, and also has some really interesting implication for fans of CR and CE.

 

What they did in [1] was feed mice either an ad lib control diet or ad lib control diet + rapamycin. Then the tested their metabolism and brown fat characteristics both after thermoneutral housing for several weeks, or after several weeks of cold exposure. 

 

The important study findings for our purposes were:

  • Cold exposure & "simulated" cold exposure via β3-adrenergic (catecholamine) receptor activation causes the browning of White Adipose Tissue (WAT) - turning it "beige" by adding mitochondria to WAT and upregulating UPC-1 expression so the WAT turns "beige" and starts burning calories, improving both glucose and lipid metabolism in the cold-exposed control mice.
  • This happens through the CE → PKA → mTOR pathway discussed here, and graphically depicted below:

tMJFr71.png

 

  • But by suppressing mTOR activity, rapamycin prevented the cold-induced browning of WAT, and as a result blocked the improvements in glucose and lipid metabolism normally associated with cold exposure, as depicted below:

3jtNvkp.png

  • Interestingly, rapamycin treatment didn't prevent the cold-induced increase of thermogenesis via expression of UCP-1 in existing BAT tissue, it just prevented WAT from turning brown/beige, apparently by suppressing mitochondrial biogenesis in WAT cells.
  • Nevertheless, the existing BAT wasn't enough, and the rapamycin-treated mice weren't able to maintain their body temperature like the control mice could when exposed to extreme cold (4 °C).

So what does all this mean, especially for people?

 

The most interesting thing is that rodents (and baby humans) have both true BAT cells (cells that were always brown, ever since they were created) and beige cells (cells that were born as WAT but have been turned brown through the addition of mitochondria and other cellular machinery). In contrast, it appears adult humans may have only beige cells [2], and no true BAT:

 

To our surprise, nearly all the human BAT abundantly expressed beige cell-selective genes, but the expression of classical brown fat-selective genes were nearly undetectable.

 

Beige or brown - so what? In fact, [3] found it doesn't make much difference thermogenically:

 

 When stimulated by such external cues [including cold exposure - DP], beige adipocytes express UCP1 protein at a similar level to classical brown adipocytes and exhibit UCP1-dependent thermogenic capacity.

 

So what difference does the pedigree of human thermogenic fat cells make?  Perhaps plenty of difference. In fact, this might explain several puzzling mysteries associated with cold exposure, and perhaps even CR.

 

First, from [3] the "browning" of white fat to beige can at least in theory happen to any normal white adipose cells if it receives the right signals, e.g. as a result of cold exposure. And, unlike true BAT cells which tend to form localized, homogeneous deposits/pads, beige cells are usually found mixed amongst white fat cells. Finally, [3] points out that "currently available devices do not have enough sensitivity and resolution to detect UCP1-positive adipocytes (i.e. BAT cells) that sporadically reside in subcutaneous WAT and other adipose depots." 

 

In other words, CE turns WAT cells to thermogenic 'beige' cells in adult humans, and these are what we call human BAT. And these beige cells may be forming anywhere in the body where WAT is deposited, not just in the neck, upper chest and upper back regions where existing PET & thermal imaging technology can detect BAT or BAT-related thermogenic activity. 

 

This could point to an answer to the mystery of how such small amounts of measurable BAT tissue (i.e. only a couple ounces in BAT+ people) can possibly account for the dramatic improvement in glucose clearance (discussed here) and increase metabolic rate (~200kcal/day, as discussed here) that is observed in people chronically exposed to cold. If beige adipose cells are more numerous than commonly believed in cold-exposed people and distributed around the body rather than concentrated only in detectable pockets of BAT, they could be contributing a lot more to thermogenesis and calorie-expenditure than seems possible based on the small amount of BAT that existing technology can detect around the neck region.  This could also explain Michael's now infamous "jiggling pecs" study [4], which found the BAT deposits near the neck account for only a small fraction of human thermogenesis in response to cold. Perhaps the neck BAT is just the tip of the iceberg... I still think sarcolipin-induced thermogenesis in skeletal muscles is the more likely explanation for where all the calories are going, but thermogenic "beige" BAT cells may be more numerous and distributed than previously believed, and therefore playing a bigger role in human cold-induced thermogenesis than anyone realizes.

 

Which brings me to the second set of puzzles that this study may solve.

 

Ever wonder why detectable human BAT tissue (I'm going to continue to use BAT, even those human BAT is really beige, not brown) has a sweet spot when it comes to BMI? On the one hand, very thin people, like anorexics and still-quite-thin recovered anorexics, have zero detectable BAT, as discussed here. But on the other hand, it is the leaner people in the normal/overweight range who have greater amounts of BAT than the really fat people, as discussed here. The upper end isn't too hard to explain via two possible mechanisms. First, obese people have more thermal insulation and so probably need less BAT than learner people to stay warm. Second, reverse causality. I.e people with BAT burn more calories, and hence remain thinner than people without BAT. So in the heavyweight range, BAT → greater thinness rather than greater thinness → BAT.

 

But why don't really skinny folks have any BAT, when they are in dire need of more thermogenesis? Recall, Speakman found that BAT was the only tissue which was increased (doubled no less!) in mass in CRed mice relative to controls [7], as discussed here. So why do skinny mice have lots of BAT, but skinny humans have none?

 

This study [1] may explain the paradox. If human BAT (really beige adipose tissue) is generated only through the 'browning' of white adipose tissue, it's no wonder it's entirely lacking in people who have extremely low levels of (white) body fat. Anorexics, and by implication, hard-core CR practitioners don't have enough WAT to convert into appreciable amounts of BAT, even when chronically cold exposed. In other words, unlike mice, humans have to have a bit of fat on their bones in order for it to be converted into BAT!  

 

And the strong apparent linkage between BAT and glucose control could explain why, in Luigi Fontana's study of human CR practitioners, those of us who were the most severely CRed paradoxically exhibited impaired glucose clearance in response to a glucose tolerance test as I discussed here. Since we have so little white fat and since we have such low Insulin/IGF-1 levels which suppresses mTOR and therefore suppressing browning of what little WAT we may have, seriously CRed humans just don't have enough BAT to help clear a large glucose load from our circulatory system during an OGTT.

 

But getting back to the study at hand [1] on rapamycin and cold exposure. It seems pretty well established that rapamycin extends lifespan in mice, perhaps by about 10% [5], by shutting down mTOR as shown in the diagram above. In striking contrast, rapamycin is pretty toxic to humans due to it's side effects as Michael discussed here, including compromised immune system and increased risk of metabolic syndrome / diabetes.

 

This discrepancy might at least in part be explained by the facts that a) mice can have both true BAT and beige adipose tissue and b) the mice in the rapamycin longevity studies (like virtually all rodent studies) were housed at temperatures that are chilly for mice. While rapamycin may have shut down the mice's ability to turn white fat into beige in [1], presumably the mice still likely had substantial true BAT deposits as a result of their cool housing conditions. And so the rapamycin-treated mice could benefit from the BAT-induced improvements in insulin sensitivity / glucose control, as well as improvements in immune system performance, and live a long time, since absent the negative side effects, mTOR suppression really is beneficial for longevity after all. The current study [1] supports this conjecture, since they found the thermogenic capacity of true BAT was not impaired by rapamycin treatment:

 

However, the respiratory capacity of BAT was 5-10 fold greater ... and was only
mildly impaired by rapamycin, suggesting that significant capacity for BAT mediated nonshivering
thermogenesis might still remain in cold-challenged, rapamycin-treated animals. 

 

In short shutting down mTOR (via rapamycin or CR) may not be so detrimental in mice because mice can maintain native BAT and BAT-thermogenesis even in the absence of mTOR activity, although not enough thermogenic capacity to keep them warm when subjected to the extreme 4°C cold challenge used in this study!  In contrast, adult humans don't have much (if any) native, true BAT, but only beige adipose tissue, and they can't even produce any of the beige fat from WAT if mTOR is shut down by CR or rapamycin. if BAT is as beneficial as I argue it is, and is indeed critical for CR to work it's magic (as I've argued herehere and here) it's no wonder rapamycin (and, heaven forbid CR...) is more toxic in humans than rodents, because only in humans does rapamycin (or severe CR) entirely prevent BAT formation.

 

Finally, this rapamycin study might explain one more seeming anomaly in the CR literature. Study [6] found that mice strains that retain the most fat when subjected to CR live the longest. Conversely, mice strains that lose the most fat have their lives cut short, rather than extended, by CR. Could it be that this correlation between CR lifespan benefits and the ability to retain some fat when CRed results from the chubbier CRed mice's ability to turn some of their remaining white fat to beneficial beige fat in the cool housing conditions of these lifespan experiments? Obviously this idea is quite speculative, but an intriguing possibility nonetheless...

 

Takeaway messages based on these studies:

  • Humans shouldn't take rapamycin unless you've had an organ transplant - in case you didn't know that already.
  • Rodents (and baby humans) have two types of thermogenic fat tissue - true BAT and "beige" adipose tissue which is white fat cells that has been "browned" - i.e. converted to a BAT-like profile by cold exposure or pharmacological means. But adult humans have only beige adipose tissue.
  • If you don't eat enough to have a little fat on your bones, you won't have sufficient WAT that can be browned, so you won't generate any BAT, even if you beat yourself up with extreme cold exposure.
  • (Speculative) CR, like rapamycin, extends lifespan in rodents at least if they are are cold-exposed, but CR may not work in humans for the following reason.  Both CR and rapamycin greatly depress mTOR activity in mice and men. Mice can still have BAT without mTOR activity, but mTOR activity is obligatory if humans are to have any BAT at all. If BAT, or more generally, the metabolic milieu created by BAT and CE, is a critical adjunct to CR as I've argued here, here and here, that means that in humans, no mTOR → no BAT → no life extension.

Fortunately, cold exposure can activate mTOR via the PKA pathway, as discussed here, so there is still hope for CR benefits in humans despite humans being so different from mice with respect to BAT formation and prevalence. But if this model is correct, for humans to benefit from CR they need to practice cold exposure and eat enough to allow mTOR to "do it's thing" of turning WAT into BAT.

 

For those of us playing around with cold exposure, it seems like that third point can't be stressed enough. And for anyone practicing CR, the last point, while speculative, seems well worth considering.

 

--Dean

 

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[1] Diabetes. 2016 Feb 8. pii: db150502. [Epub ahead of print]

 
Rapamycin blocks induction of the thermogenic program in white adipose tissue.
 
Tran CM(1), Mukherjee S(1), Ye L(2), Frederick DW(1), Kissig M(3), Davis JG(1),
Lamming DW(4), Seale P(3), Baur JA(5).
 
Rapamycin extends lifespan in mice, yet paradoxically causes lipid dysregulation 
and glucose intolerance through mechanisms that remain incompletely understood.
Whole body energy balance can be influenced by beige/brite adipocytes, which are 
inducible by cold and other stimuli via β-adrenergic signaling in white adipose
depots. Induction of beige adipocytes is considered a promising strategy to
combat obesity because of their ability to metabolize glucose and lipids,
dissipating the resulting energy as heat through uncoupling protein 1 (UCP1).
Here, we report that rapamycin blocks the ability of β-adrenergic signaling to
induce beige adipocytes and expression of thermogenic genes in white adipose
depots. Rapamycin enhanced transcriptional negative feedback on the β3-adrenergic
receptor. However, thermogenic gene expression remained impaired even when the
receptor was bypassed with a cell-permeable cAMP analogue, revealing the
existence of a second inhibitory mechanism. Accordingly, rapamycin-treated mice
are cold-intolerant, failing to maintain body temperature and weight when shifted
to 4 °: C. Adipocyte-specific deletion of the mTORC1 subunit Raptor recapitulated
the block in beta-adrenergic signaling. Our findings demonstrate a positive role 
for mTORC1 in the recruitment of beige adipocytes and suggest that inhibition of 
β-adrenergic signaling by rapamycin may contribute to its physiological effects.
 
© 2016 by the American Diabetes Association. Readers may use this article as long
as the work is properly cited, the use is educational and not for profit, and the
work is not altered.
 
PMCID: PMC4806661 [Available on 2017-04-01]
PMID: 26858361
 
------------
[2] PLoS One. 2012;7(11):e49452. doi: 10.1371/journal.pone.0049452. Epub 2012 Nov 16.
 
Human BAT possesses molecular signatures that resemble beige/brite cells.
 
Sharp LZ(1), Shinoda K, Ohno H, Scheel DW, Tomoda E, Ruiz L, Hu H, Wang L,
Pavlova Z, Gilsanz V, Kajimura S.
 
Author information: 
(1)UCSF Diabetes Center and Department of Cell and Tissue Biology, University of 
California San Francisco, San Francisco, California, USA.
 
Brown adipose tissue (BAT) dissipates chemical energy and generates heat to
protect animals from cold and obesity. Rodents possess two types of UCP-1
positive brown adipocytes arising from distinct developmental lineages:
"classical" brown adipocytes develop during the prenatal stage whereas "beige" or
"brite" cells that reside in white adipose tissue (WAT) develop during the
postnatal stage in response to chronic cold or PPARγ agonists. Beige cells'
inducible characteristics make them a promising therapeutic target for obesity
treatment, however, the relevance of this cell type in humans remains unknown. In
the present study, we determined the gene signatures that were unique to
classical brown adipocytes and to beige cells induced by a specific PPARγ agonist
rosiglitazone in mice. Subsequently we applied the transcriptional data to humans
and examined the molecular signatures of human BAT isolated from multiple adipose
depots. To our surprise, nearly all the human BAT abundantly expressed beige
cell-selective genes, but the expression of classical brown fat-selective genes
were nearly undetectable. Interestingly, expression of known brown fat-selective 
genes such as PRDM16 was strongly correlated with that of the newly identified
beige cell-selective genes, but not with that of classical brown fat-selective
genes. Furthermore, histological analyses showed that a new beige cell marker,
CITED1, was selectively expressed in the UCP1-positive beige cells as well as in 
human BAT. These data indicate that human BAT may be primary composed of
beige/brite cells.
 
PMCID: PMC3500293
PMID: 23166672
 
---------
[3] J Clin Invest. 2015 Feb;125(2):478-86. doi: 10.1172/JCI78362. Epub 2015 Feb 2.
 
Brown and beige fat in humans: thermogenic adipocytes that control energy and
glucose homeostasis.
 
Sidossis L, Kajimura S.
 
Brown adipose tissue (BAT), a specialized fat that dissipates energy to produce
heat, plays an important role in the regulation of energy balance. Two types of
thermogenic adipocytes with distinct developmental and anatomical features exist 
in rodents and humans: classical brown adipocytes and beige (also referred to as 
brite) adipocytes. While classical brown adipocytes are located mainly in
dedicated BAT depots of rodents and infants, beige adipocytes sporadically reside
with white adipocytes and emerge in response to certain environmental cues, such 
as chronic cold exposure, a process often referred to as "browning" of white
adipose tissue. Recent studies indicate the existence of beige adipocytes in
adult humans, making this cell type an attractive therapeutic target for obesity 
and obesity-related diseases, including type 2 diabetes. This Review aims to
cover recent progress in our understanding of the anatomical, developmental, and 
functional characteristics of brown and beige adipocytes and discuss emerging
questions, with a special emphasis on adult human BAT.
 
PMCID: PMC4319444
PMID: 25642708 
 
--------------
[4] Eur J Nucl Med Mol Imaging. 2016 Mar 19. [Epub ahead of print]
 
Human brown adipose tissue [(15)O]O2 PET imaging in the presence and absence of
cold stimulus.
 
U Din M(1,)(2), Raiko J(1,)(2), Saari T(1,)(2), Kudomi N(3), Tolvanen T(1,)(2),
Oikonen V(1,)(2), Teuho J(1,)(2), Sipilä HT(1,)(2), Savisto N(1,)(2), Parkkola
R(4), Nuutila P(1,)(2), Virtanen KA(5,)(6).
 
 
PURPOSE: Brown adipose tissue (BAT) is considered a potential target for
combatting obesity, as it produces heat instead of ATP in cellular respiration
due to uncoupling protein-1 (UCP-1) in mitochondria. However, BAT-specific
thermogenic capacity, in comparison to whole-body thermogenesis during cold
stimulus, is still controversial. In our present study, we aimed to determine
human BAT oxygen consumption with [(15)O]O2 positron emission tomography (PET)
imaging. Further, we explored whether BAT-specific energy expenditure (EE) is
associated with BAT blood flow, non-esterified fatty acid (NEFA) uptake, and
whole-body EE.
METHODS: Seven healthy study subjects were studied at two different scanning
sessions, 1) at room temperature (RT) and 2) with acute cold exposure.
Radiotracers [(15)O]O2, [(15)O]H2O, and [(18)F]FTHA were given for the
measurements of BAT oxygen consumption, blood flow, and NEFA uptake,
respectively, with PET-CT. Indirect calorimetry was performed to assess
differences in whole-body EE between RT and cold.
RESULTS: BAT-specific EE and oxygen consumption was higher during cold stimulus
(approx. 50 %); similarly, whole-body EE was higher during cold stimulus (range
2-47 %). However, there was no association in BAT-specific EE and whole-body EE. 
BAT-specific EE was found to be a minor contributor in cold induced whole-body
thermogenesis (almost 1 % of total whole-body elevation in EE). Certain deep
muscles in the cervico-thoracic region made a major contribution to this
cold-induced thermogenesis (CIT) without any visual signs or individual
perception of shivering. Moreover, BAT-specific EE associated with BAT blood flow
and NEFA uptake both at RT and during cold stimulus.
CONCLUSION: Our study suggests that BAT is a minor and deep muscles are a major
contributor to CIT. In BAT, both in RT and during cold, cellular respiration is
linked with circulatory NEFA uptake.
 
PMID: 26993316
 
-------------
[5] Nature. 2009 Jul 16;460(7253):392-5. doi: 10.1038/nature08221. Epub 2009 Jul 8.
 
Rapamycin fed late in life extends lifespan in genetically heterogeneous mice.
 
Harrison DE(1), Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL,
Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, Miller RA.
 
Author information: 
(1)The Jackson Laboratory, Bar Harbor, Maine 04609, USA. david.harrison@jax.org
 
Comment in
    Nature. 2009 Jul 16;460(7253):331-2.
 
Inhibition of the TOR signalling pathway by genetic or pharmacological
intervention extends lifespan in invertebrates, including yeast, nematodes and
fruitflies; however, whether inhibition of mTOR signalling can extend lifespan in
a mammalian species was unknown. Here we report that rapamycin, an inhibitor of
the mTOR pathway, extends median and maximal lifespan of both male and female
mice when fed beginning at 600 days of age. On the basis of age at 90% mortality,
rapamycin led to an increase of 14% for females and 9% for males. The effect was 
seen at three independent test sites in genetically heterogeneous mice, chosen to
avoid genotype-specific effects on disease susceptibility. Disease patterns of
rapamycin-treated mice did not differ from those of control mice. In a separate
study, rapamycin fed to mice beginning at 270 days of age also increased survival
in both males and females, based on an interim analysis conducted near the median
survival point. Rapamycin may extend lifespan by postponing death from cancer, by
retarding mechanisms of ageing, or both. To our knowledge, these are the first
results to demonstrate a role for mTOR signalling in the regulation of mammalian 
lifespan, as well as pharmacological extension of lifespan in both genders. These
findings have implications for further development of interventions targeting
mTOR for the treatment and prevention of age-related diseases.
 
PMCID: PMC2786175
PMID: 19587680
 
------------
[6] Aging Cell. 2011 Aug;10(4):629-39. doi: 10.1111/j.1474-9726.2011.00702.x. Epub
2011 Apr 25.
 
Fat maintenance is a predictor of the murine lifespan response to dietary
restriction.
 
Liao CY(1), Rikke BA, Johnson TE, Gelfond JA, Diaz V, Nelson JF.
 
Author information: 
(1)Department of Physiology, University of Texas Health Science Center, San
Antonio, TX 78229, USA.
 
Dietary restriction (DR), one of the most robust life-extending manipulations, is
usually associated with reduced adiposity. This reduction is hypothesized to be
important in the life-extending effect of DR, because excess adiposity is
associated with metabolic and age-related disease. Previously, we described
remarkable variation in the lifespan response of 41 recombinant inbred strains of
mice to DR, ranging from life extension to life shortening. Here, we used this
variation to determine the relationship of lifespan modulation under DR to fat
loss. Across strains, DR life extension correlated inversely with fat reduction, 
measured at midlife (males, r= -0.41, P<0.05, n=38 strains; females, r= -0.63,
P<0.001, n=33 strains) and later ages. Thus, strains with the least reduction in 
fat were more likely to show life extension, and those with the greatest
reduction were more likely to have shortened lifespan. We identified two
significant quantitative trait loci (QTLs) affecting fat mass under DR in males
but none for lifespan, precluding the confirmation of these loci as coordinate
modulators of adiposity and longevity. Our data also provide evidence for a QTL
previously shown to affect fuel efficiency under DR. In summary, the data do not 
support an important role for fat reduction in life extension by DR. They suggest
instead that factors associated with maintaining adiposity are important for
survival and life extension under DR.
 
© 2011 The Authors. Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society
of Great Britain and Ireland.
 
PMCID: PMC3685291
PMID: 21388497
 
------------
[7] Mech Ageing Dev. 2005 Jun-Jul;126(6-7):783-93. Epub 2005 Mar 16.
 
Energy expenditure of calorically restricted rats is higher than predicted from
their altered body composition.
 
Selman C(1), Phillips T, Staib JL, Duncan JS, Leeuwenburgh C, Speakman JR.
 
Author information: 
(1)University of Florida, Department of Aging and Geriatric Research, College of 
Medicine, Gainesville, 32608, USA. c.selman@ucl.ac.uk
 
Debate exists over the impact of caloric restriction (CR) on the level of energy 
expenditure. At the whole animal level, CR decreases metabolic rates but in
parallel body mass also declines. The question arises whether the reduction in
metabolism is greater, smaller or not different from the expectation based on
body mass change alone. Answers to this question depend on how metabolic rate is 
normalized and it has recently been suggested that this issue can only be
resolved through detailed morphological investigation. Added to this issue is the
problem of how appropriate the resting energy expenditure is to characterize
metabolic events relating to aging phenomena. We measured the daily energy
demands of young and old rats under ad libitum (AD) food intake or 40% CR, using 
the doubly labeled water (DLW) method and made detailed morphological examination
of individuals, including 21 different body components. Whole body energy demands
of CR rats were lower than AD rats, but the extent of this difference was much
less than expected from the degree of caloric restriction, consistent with other 
studies using the DLW method on CR animals. Using multiple regression and
multivariate data reduction methods we built two empirical predictive models of
the association between daily energy demands and body composition using the ad
lib animals. We then predicted the expected energy expenditures of the CR animals
based on their altered morphology and compared these predictions to the observed 
daily energy demands. Independent of how we constructed the prediction, young and
old rats under CR expended 30 and 50% more energy, respectively, than the
prediction from their altered body composition. This effect is consistent with
recent intra-specific observations of positive associations between energy
metabolism and lifespan and theoretical ideas about mechanisms underpinning the
relationship between oxygen consumption and reactive oxygen species production in
mitochondria.
 
PMID: 15888333

There will never be peace in the world while there are animals in our bellies.

#210 TomBAvoider

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Posted 15 April 2016 - 05:21 PM

Remarkable finds and very, very important in enlarging our knowledge of the effects of CR - and highly relevant to us, CRONies. I have personally noticed that at my lowest weight, when I practiced my most restricted CR, my QOL took a dip compared to slightly higher BMI, and more significantly, my blood panel numbers wrt. glucose also got worse. I found that very puzzling, as I read repeatedly how more CR is better (short of actual starvation), and mice on CR70 were doing better than f.ex. CR30. Now, at my strictest, I don't think I ever exceeded CR50, because at that point I was on 1060 cal/day - which is right about 50% of the recommended 2200 cal/day for a mildly active ad lib man. Which meant that I had plenty of room to CR70. And yet, my sense of well-being, and more crucially objective blood panel numbers were better on 1390 cal/day. At which point, I decided that linear extrapolation from rodents to humans probably is not warranted, or at least we don't have enough science to recommend going below that level. Ever since I've hovered between 1400 - 1500 a day - and felt best on it - though there is one wrinkle in that calorie number, as the 1400-1500 number is true for 5 days a week, because I've incorporated one half-fast day where I limit myself to 900 cal/day and one full day of 0 calories; this averages over a full week to some 1200 cal/day, but I feel somehow the dynamics of fasting don't translate straightforwardly to averaging of calories over fasted and non-fasted days.

 

That said, and acknowledging all the valuable information about rapa, that you have found so spectacularly, I feel that you have been a bit hasty in your conclusions about rapa. You state, as if uncontroversial, that rapa is immunosuppressive. You also link to a post by MR on some negatives of rapa for humans. You really should have been digging deeper. As you, of all people, must appreciate, sometimes knowing more leads you to the very opposite conclusion, which is why it can be dangerous to base one's actions on incomplete information - we might be doing more harm than good.

 

The issue is readily apparent when you cite the MR link - at the time of the original discussion of rapa in humans as an aid in longevity, I made a number of objections to MR's post - in the link you provide, he even references those objections, but again does not address them. Now it is possible that he has excellent answers to those objections, but short of stating them, we are still left at an impasse. Unfortunately my objections and the studies I used to bolster them have been lost to the mists of time and disappeared archives, but in the briefest of references, my objections were centered around the extremely fundamental fact that you cannot make blanket statements about the effect of a drug without carefully referencing the dosage. It's the oldest principle in medicine: "the dose makes the poison" (Paracelsus). This is so fundamental and uncontroversial that I find it astonishing that folks are not doing it for rapa, while discussing dosage at great length for every other drug, whether aspirin or alcohol. Of course, my objection was not centered around the mere principle, but actual research results with differing dosages - unfortunately, there is not much research and that's a tragic state of affairs, one wishes there were a lot more, but the absence of research should not be used to bolster the wobbly conclusions of the status quo ("rapa is immunosuppressive"). The immune system is highly dependent on these very effects of dosage - the entire hormetic effect rests on this, not to mention the principle of vaccination.

 

The idea that rapa is immunosuppressive is based on the experience of organ transplant patients having more cancer and generally exhibiting symptoms of a compromised immune system. Hence the conclusion - rapa is immunosuppressive. This actually qualifies as a genuinely comical example of circular reasoning. The goal was to repress the immune system so that a transplant organ would not be rejected, and in service of that goal we administered massive doses of a drug until the point where we did achieve the goal of immunosuppression - and then we turned around and disapprovingly point to that suppression as proof that the drug is deleterious because we've reached the goal! I nominate water as the latest dangerous substance to consume, based on those cases where people induced hyponatremia by quickly consuming massive quantities of water and then dying. Clearly, water is a killer, and so is alcohol when college kids drink absurd quantities in one sitting. Of course, if you try your darndest to reach a goal, you'll reach it, but then don't complain that you've reached it. So yes, with massive doses of rapa designed to compromise the immune system, we - DUH! - managed to compromise the immune system and the consequences were increased cancer among other effects of a compromised immune system. However, what if we lowered the dosage? There was a study showing rapa to be cancer-protective at lower dosages, although it was unclear as to whether that was a global effect of priming the immune system through a hormetic effect, or a more direct pathway - unfortunately I can't locate the study at the moment, but another study found this:

 

http://www.ncbi.nlm....pubmed/19249557

 

Transplant Proc. 2009 Jan-Feb;41(1):359-65. doi: 10.1016/j.transproceed.2008.10.090.

 

Effect of low-dose rapamycin on tumor growth in two human hepatocellular cancer cell lines.

Abstract

 

AIM:

Liver transplantation is the best treatment for patients with early hepatocellular carcinoma (HCC) and cirrhosis. A limiting factor for long-term survival remains posttransplant tumor recurrence. Thus, there is widespread discussion about the role of various immunosuppressive agents. The newly developed immunosuppressive drug rapamycin may aid to lower recurrence rates. We investigated the efficiency of rapamycin as compared with previous immunosuppressants in a tumor cell model.

 

METHODS:

We studied two HCC cell lines for cell-cycle and proliferation analyses after treatment with rapamycin or other immunosuppressants. To elucidate the underlying molecular signaling pathway, we performed Western blotting for phosphorylated p70 S6 kinase protein expression.

 

RESULTS:

Low-dose rapamycin inhibited tumor cell growth at doses of 1, 5, and 10 ng/mL, while standard immunosuppressants stimulated growth. A rapamycin dose of 20 ng/mL showed a marked decrease in the growth inhibition of both HCC cell lines compared to low-dose administration.

 

CONCLUSION:

Rapamycin in low doses inhibited the growth of two HCC cell lines in vitro. Inhibition of tumor cell growth was observed with a high dose of rapamycin (20 ng/mL), which appears to be the dividing line between growth and inhibition. We postulated that at higher doses the immunosuppressive effect of rapamycin is overrode by its antitumor effects.

PMID:19249557 [PubMed - indexed for MEDLINE]

 

There are of course other effects, such as on glucose metabolism and lipids etc., but again - people, for crying out loud - AT WHAT DOSAGE?? Any conclusions about rapa and morbidities and biomarkers such as diabetes, insulin response, hyperlipidemia - in this case all drawn from severely immunosuppressed transplant patients are by definition impossible to draw, except that at very high dosages, in addition to immunosuppression such massive dosages of rapa can result in diabetes and other problems. And water can kill too. How do we know that it is not the same as with cancer and rapa dosage? That at appropriate dosage rapa can boost the immune system, or cut down on cancer, or give us better glucose control and greater insulin sensitivity and a superior lipid profile etc.? Maybe low dose rapa give us *superior* glucose and lipid metabolism?

 

Without discussing the dosage - whether of rapa or water or aspirin - the resulting conclusions are going to be highly limited. All we can say is that at dosages high enough to suppress the immune system, rapa will suppress the immune system. And that when the dosage is so high as to suppress the immune system it can also result in other unfavorable effects including diabetes. 

 

The other aspect of this is that it is often unrealistic to affect a complex biological system for a specific goal with a single "silver bullet". It is a dream of humanity since ancient times that there should be a single silver bullet, an ambrosia drink of the gods, a fountain of youth, a philosopher's stone to accomplish extremely complex goals - health, longevity, wealth. It's not realistic from a dynamic systems point of view. It is therefore highly likely that rapa by itself may not result in appreciable (or any) extension of max life span. That may be true for any one substance (say, metformin). However, what if it were possible to combine multiple drugs with other interventions (the way it's possible to combine CR with CE) to accomplish such a complex goal in a dynamic system? There is a reason why doctors often prescribe multiple drugs which counteract various negative side effects - the hope is that the NET will be positive. Same here - it is really no different at all. Say rapa results in glucose intolerance - maybe combining with metformin could take care of that? In fact, when discussing this, I proposed a cocktail of drugs with rapa, metformin, melatonin, vaccination against pneumonia and so forth.

 

However, before we even get so far as designing a complex multi drug regiment combined with other interventions, we must establish threshold effects. At what precise dosage does rapa exhibit life extending effects? Before or after undesirable side effects (IN HUMANS!) of suppressed immune system, diabetes etc.? If before (i.e. there are doses low enough to prolong lifespan but not high enough to result in compromised immune function or diabetes etc.), then can we push this effect higher by combining with other drugs? So f.ex. we gain 5 years with a low dose of no side effects, but a higher dose would give us 10 years if we can mitigate the side effects with other drugs. This is why it is so important to establish threshold points.

 

Same with the whole rapa/BAT issue - at what dose? Is it really the case, as apparently with arsenic - any amount is bad - or maybe there are the well-known flip effects, lower dosage might result in *superior* engagement of BAT tissue (btw. once upon a time the consensus was that any amount of radiation is bad - today we believe that a small amount might be actively good, but in any case there is a threshold effect of harm). It would be useful to see the impact of rapa on BAT at varying dosages. And then maybe see if there are other drugs or therapies or interventions that may extend the benefits of rapa without impacting BAT negatively.

 

Bottom line, without a more nuanced look at rapa, we should not jump to conclusions. 



#211 Dean Pomerleau

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Posted 15 April 2016 - 06:45 PM

Tom,

 

Good point. I may have been too hasty - extrapolating from the effects of high-dose rapamycin in transplant patients to dismiss rapamycin as a potential life-extension drug at low enough doses. That'll teach me to listen to Michael's analysis .

 

But nevertheless I think the main point of my argument stands - rapamycin may have quite different effects wrt life extension in rodents vs. humans, since mice can maintain BAT while taking rapamycin while it doesn't look like people can.

 

So, when you say:

 At what precise dosage does rapa exhibit life extending effects? Before or after undesirable side effects (IN HUMANS!) of suppressed immune system, diabetes etc.?

 

I presume you mean "At what precise dosage does rapa exhibit life extending effects in rodents?" since we'll won't have human lifespan trials (with rapamycin or anything else) in our lifetime.

 

And my response would be - what gives you confidence that a life extending effect of rapamycin in rodents will carry over to humans, even if we factor out overt negative side effects (like immunosuppression) that may or may not occur at the human-equivalent of the life-extending dosage in rodents?

 

In other words, it looks like rapamycin will have a different impact on BAT expression in human vs rodents - rapamycin will probably eliminate BAT in humans, but it doesn't eliminate it (entirely) in mice. If BAT and/or thermogenesis is important for health/longevity as I've been arguing, rapamycin may be harmful (or neutral) for human lifespan even if it makes rodents live longer. This seems like an instance where it may be very difficult to extrapolate rodent results to humans.

 

Bottom line, without a more nuanced look at rapa, we should not jump to conclusions. 

 

Bottom line, until we can eliminate the hypothesis that BAT (or thermogenesis) is important for lifespan, or show rapamycin doesn't eliminate BAT in humans, I'd consider even low-dose rapamycin a non-starter, independent of any other negative side effects it may or may not have.

 

Note at this point I'd say the same thing about serious CR - which at 1200kcal per day you certainly qualify for!

 

CR suppresses mTOR, like rapamycin does. Until we can eliminate the hypothesis that BAT (or thermogenesis) is important for lifespan, or show rapamycin serious CR doesn't eliminate BAT in humans, I'd consider even low-dose rapamycin serious CR a non-starter, independent of any other negative side effects it may or may not have. 

 

--Dean


There will never be peace in the world while there are animals in our bellies.

#212 TomBAvoider

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Posted 15 April 2016 - 07:34 PM

[...]

Bottom line, until we can eliminate the hypothesis that BAT (or thermogenesis) is important for lifespan, or show rapamycin doesn't eliminate BAT in humans, I'd consider even low-dose rapamycin a non-starter, independent of any other negative side effects it may or may not have.

 

Note at this point I'd say the same thing about serious CR, which suppresses mTOR like rapamycin does. Until we can eliminate the hypothesis that BAT (or thermogenesis) is important for lifespan, or show rapamycin serious CR doesn't eliminate BAT in humans, I'd consider even low-dose rapamycin serious CR a non-starter, independent of any other negative side effects it may or may not have. 

 

--Dean

 

The thermogenesis hypothesis may be correct in that BAT is important for lifespan, but in the interest of precision if nothing else, I think one can qualify your conclusions somewhat. If, rapa negates the BAT pathway, but prolongs life along a different pathway to end up with a net extension over BAT, it may still be worth it, but there is no way of knowing at the moment. More interesting to me is the mechanism of action of rapa on BAT and BAT-like tissue. I mean in the same way that if f.ex. rapa were to extend human life except unfortunately it doesn't because, say, it causes diabetes as a side effect so the net effect on life extension is a wash, if f.ex. metformin would take care of that side effect, then we'd reap the benefit without the negative consequence and the net would be in favor of extension. Again, I come back to my instinctive belief that we are not going to impact aging appreciably with just ONE drug or intervention - in a dynamic system, that is not likely. There have to be multiple interventions - similar to how you don't go to repair a complex machine like a computer only equipped with a hammer (or worse, high dose hammer like a sledgehammer), a hammer is a fine tool, but you need more. What if we could modify the effect of rapa on BAT in humans (through some other drug or intervention - to speculate wildly f.ex. if we managed to modify fat cells to become TRUE brown BAT like in rodents) and thus even if BAT were critical to LE in humans, rapa might yet be a useful intervention. So I wouldn't make a blanket statement like the one of yours I quoted above.

 

Looking at the studies you cited, f.ex. PMID: 19587680 - I looked at the full study and to quote: "Rapamycin reduces function of the rapamycin target kinase TOR and has anti-neoplastic activities[...]" - as I stated above, if this is true for humans as it is for mice (and as I mentioned in my previous post there are reasons to suspect it's possible), then this is an example of "if rapa negates the BAT pathway, but prolongs life along a different pathway", as long as the net is higher LE than with BAT alone. What is the LE in mice due to? In PMID: 19587680 they say: "Rapamycin may extend lifespan by postponing death from cancer, by retarding mechanisms of ageing, or both." If we cut down on cancer and achieve LE in humans, is that valid? To what degree is there more or less LE based on the BAT pathway, or the cancer-inhibition pathway? Or is BAT activation also necessary to inhibit cancer (unlikely)? So that's my answer to: "what gives you confidence that a life extending effect of rapamycin in rodents will carry over to humans" - if rapa can cut down on cancer in humans (which is testable within our lifetimes), without negatively impacting other aspects of health, then through that mechanism alone it might lead to (modest) LE in humans

 

More properly then, one could position rapa as one of those interventions that is unfortunately not synergistic but antagonistic to LE through CE. So you can have LE through CE, or LE through rapa, but not LE through both. The example here would be ad lib people who are not practicing CE who might achieve a measure of LE through rapa alone without bothering to attempt any blocking of rapa action on the BAT pathway.

 

Before commenting further, I need to digest PMID: 26858361 - I want to know both mechanisms of rapa inhibition of thermogenic gene expression, seeing as one was bypassed; if one can successfully do that so that the entire effect is obviated, then I don't see why rapa would not be back in play for those who practice CE.


Edited by TomBAvoider, 15 April 2016 - 07:40 PM.


#213 TomBAvoider

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Posted 15 April 2016 - 08:08 PM

Given that many LE drugs and interventions cannot be practically studied in humans, and all we are left with are studies in animals, the entire topic of the translatability of findings from animals to humans takes on a huge importance. How do you know when a study in rodents is applicable to humans (as you say, Dean wrt. rapa "what gives you confidence that a life extending effect of rapamycin in rodents will carry over to humans" - which can fairly be asked of the BAT effect just as well... what gives you confidence?). Especially when it comes to things lower than mammals, I simply tend to dismiss such studies from the point of view of actionable info for CRON practices. However, the question is valid: what translates? 

 

Perhaps a clue might be: if the intervention affects the same genes in both the study animal and the human (they share those particular genes), the chance of translatability might be higher. There are mapping efforts to see what is shared across the animal kingdom - here is a neat graphic:

 

https://www.scienced...60413120951.htm

 

"In wide range of species, longevity proteins affect dozens of the same genes

 

Scientists studying the biology of aging have found dozens of genes common to worms, flies, mice and humans that are all affected by the same family of proteins."



#214 Gordo

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Posted 16 April 2016 - 08:53 AM

A new study looking at the "Effects of L-Citrulline Supplementation on Arterial Stiffness, Pressure Wave Reflection, and Cardiac Autonomic Responses to Acute Cold Exposure with Isometric Exercise" may indicate eating more watermelon is in order (didn't know you should eat the rinds too by the way, I will try that)...

 

p.s. Dean to answer your question about temp logging - I know it wouldn't be ideal, but I think just a single point plot of body temps throughout the day might be useful during CE experimentation to see what activities elicit the largest thermogenesis (TG) response.  I'm less interested in temperature deltas between various organs although that would also be useful...



#215 Dean Pomerleau

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Posted 16 April 2016 - 12:41 PM

TomB,

 

You wrote:

I come back to my instinctive belief that we are not going to impact aging appreciably with just ONE drug or intervention - in a dynamic system, that is not likely. 

 

I agree with this belief 100%. No single, isolated tweak to metabolism is going to dramatically impact longevity, at least not positively. Metabolism is just too damn complicated

 

But where I start to part company with you is when you say stuff like:

There have to be multiple interventions - similar to how you don't go to repair a complex machine like a computer...  In fact, when discussing this, I proposed a cocktail of drugs with rapa, metformin, melatonin, vaccination against pneumonia and so forth.

 

The human body is (unfortunately) not much like a complex, human-created machine. Machines, even incredibly complex ones like the microprocessors designed by Intel (where I formerly worked for a time) or a Boeing 747, only work and are serviceable to the extent they have been engineered using modular, scalable, and well-documented design processes. The only thing of intentional human origin that even resembles human metabolism is legacy computer software, so call "spaghetti-code" in which not only the documentation, but the source code has been lost, and the original programmer is long dead. A good example is the air traffic control system for US airspace.  It is combination of hardware, software, and human best practices that has evolved and accreted over the last 50 years. It works reasonably well, but has definite limitations and threatens to hamper innovations, like civilian drones, because it just can't handle any increase in load. Unfortunately we're stuck with it because it's so "mission critical" we can't shut it down to do a major overhaul, and it is so complicated and fraught with interdependencies that improving it piecemeal threatens to bring the whole thing crashing down (literally and figuratively).

 

It seems like a hubristic pipe dream to me to think that we know enough about the interdependencies and hidden side effects of multi-drug cocktails to intervene effectively to increase human longevity, when even as simple and seemingly harmless cocktail of creatine + caffeine may have negative effects that neither exhibits on their own (PMID: 26366971).

 

FWIW, Aubrey de Grey seems to think the same way, as expressed in this Q&A:

 
Q: You comment in your talks that tinkering with metabolism is not a viable approach, because it is too complicated and impossible to modify without causing "more harm than good". However, it seems a number of anti aging companies, focused on drugs and genetic engineering, seem to be pursuing this route. Can you explain this disagreement?
 
Aubrey: Great question. The short answer is that there is one exception to my comment, but it’s an exception that doesn’t seem likely to have much practical significance for humans. The exception is calorie restriction. The drugs and other simple interventions (including genetic ones) that companies are looking at are almost all focused on making the body behave as if it is in a famine. The motivation, of course, is that famine (and these drugs) can greatly postpone aging in short-lived laboratory organisms like mice, rats and (even more so) worms. But it turns out - and for very obvious evolutionary reasons - that this doesn’t work nearly so well in long-lived species as in short-lived ones. The most that I think humans can possibly benefit by that kind of approach is a couple of years. 

 

I agree with Aubrey It's most likely futile to try to tweak metabolism using pharmacological interventions formulated as single drugs or multi-drug cocktails whose components we hope will make up for each other's shortcomings and negative side effects. It's like trying to patch spaghetti-code to mask a bug you don't really understand.

 

Unlike Aubrey however, I'm not so sure his SENS approach is a better answer, or is much of a step up from this strategy. It too tries to work around the edges of metabolism, trying to clean up the damage done by "bugs" we don't understand. It might work for a while, but it's only a patchwork solution to keep the system working until it can be redesigned from scratch to be more resilient and maintainable. And if the bugs are too numerous, or too interdependent, it will take forever to squash them individually. I've not heard much of an answer from Michael or Aubrey to this open question - namely, just how many metabolic bugs will need to be squashed before meaningful human life extension can be achieved? All I've heard from Aubrey on the topics is "To get more than about 15 years we'd definitely need to have at least reasonably effective repair of all seven categories" which seems to me like a tall order indeed!

 

Rather than betting on a magic drug cocktail or expecting Aubrey and Co. to engineer reasonably effective repair for all seven categories of aging damage within my healthy lifetime, it seems to me our best hope is to embrace and leverage what we've already got - namely our genetic endowment, spaghetti-code and all.

 

Aubrey dismisses the idea that humans have retained, or will benefit much from, the systemic "hunkered down" metabolic state that CR triggers. He says our ancestors didn't need it to the same extent that rodents needed it to survive and procreate effectively, so the "CR response" will have been jettisoned from the human genome. I think Aubrey's perspective on this is mistaken. Luigi Fontana has shown [1] that long-term human CR practitioners exhibit a similar gene expression profile and quite a few of the same changes in biomarkers that are associated with extended longevity in CRed rodents. For example, just like it does in rodents, CR in humans inhibits the IGF-1 → AKT → mTOR pathway we've been discussing on this thread a lot lately.  So there is hope for human CR doing something good...

 

BUT, based on all the evidence explored in this thread, I have a strong suspicion that calorie restriction alone will be insufficient to reproduce in humans the longevity benefits observed in rodents. The reason is simply, it's not just CR that researchers have been subjecting rodents too all these years with beneficial results - it's CR plus cold exposure. It makes sense from an evolutionary perspective, since CR and CE would have been frequently conjoined in our evolutionary past, as discussed here. And the metabolic adjustments made by CR and CE appear to be eerily complementary, both at the systemic and mitochondrial level. And most importantly, experiments testing one without the other have failed to extend lifespan in rodents (PMID: 9032756) as discussed herehere, and here.

 

I think about the "cocktail" of CR1 + CE + copious exercise this way. This combination is not like trying to poke around with the original source code to patch a bug you don't understand. And it's not like trying to play whack-a-mole with the damage created by a poorly designed system subjected to inputs it wasn't designed to handle - i.e. over-nutrition & under-exertion in a constantly warm environment. 

 

Instead, CR1 + CE + exercise is a cocktail designed to mimic the environmental input our genes have already been tuned to handle in order to help our starving mammalian ancestors vigorously and nearly-continuously forage for food in a cold environment so as to survive a few more weeks of winter. We see the benefits of this "cocktail" in action in the natural world all around us - within a species individuals living in colder climates live longer than those living in more temperate conditions, and this holds across the entire animal kingdom (PMID: 19666552).

 

So the idea is rather than trying to patch the spaghetti-code (via pharma cocktails), or clean up the mess it creates (via the SENS strategy), to instead get the inputs to the system right (CR + CE + EX) and hope that our spaghetti-code genetic program will do the rest, helping us to live long enough for a better solution to come alone...

 

--Dean

 

------

1When I refer to "CR" in this context I mean net calorie restriction - i.e. "calories in - calories out", rather than absolute calorie restriction. Specifically, CR to the degree that it results in a low BMI and low glucose/insulin/IGF-1, while still providing enough energy to support BAT synthesis & thermogenesis, along with lots of exercise.

 

-----------

[1] Aging Cell. 2013 Aug;12(4):645-51. doi: 10.1111/acel.12088. Epub 2013 Jun 5.
Calorie restriction in humans inhibits the PI3K/AKT pathway and induces a younger
transcription profile.
 
Mercken EM(1), Crosby SD, Lamming DW, JeBailey L, Krzysik-Walker S, Villareal DT,
Capri M, Franceschi C, Zhang Y, Becker K, Sabatini DM, de Cabo R, Fontana L.
 
Author information:
(1)Laboratory of Experimental Gerontology, National Institute on Aging, National
Institutes of Health, Baltimore, MD 21224, USA.
 
Caloric restriction (CR) and down-regulation of the insulin/IGF pathway are the
most robust interventions known to increase longevity in lower organisms.
However, little is known about the molecular adaptations induced by CR in humans.
Here, we report that long-term CR in humans inhibits the IGF-1/insulin pathway in
skeletal muscle, a key metabolic tissue. We also demonstrate that CR induces
dramatic changes of the skeletal muscle transcriptional profile that resemble
those of younger individuals. Finally, in both rats and humans, CR evoked similar
responses in the transcriptional profiles of skeletal muscle. This common
signature consisted of three key pathways typically associated with longevity:
IGF-1/insulin signaling, mitochondrial biogenesis, and inflammation. Furthermore,
our data identify promising pathways for therapeutic targets to combat
age-related diseases and promote health in humans.
 
© 2013 John Wiley & Sons Ltd and the Anatomical Society.
 
PMCID: PMC3714316
PMID: 23601134

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#216 AlPater

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Posted 16 April 2016 - 02:16 PM

There is much more in the below paper than that on cold exposure.

 

 

Nutrition and Energetics in Rodent Longevity Research.
Gibbs VK, Smith DL Jr.
Exp Gerontol. 2016 Apr 9. pii: S0531-5565(16)30093-6. doi: 10.1016/j.exger.2016.04.004. [Epub ahead of print]
PMID: 27073168
 
Abstract
 
The impact of calorie amount on aging has been extensively described; however, variation over time and among laboratories in animal diet, housing condition, and strains complicates discerning the true influence of calories (energy) versus nutrients on lifespan. Within the dietary restriction field, single macronutrient manipulations have historically been researched as a means to reduce calories while maintaining adequate levels of essential nutrients. Recent reports of nutritional geometry, including rodent models, highlight the impact macronutrients have on whole organismal aging outcomes. However, other environmental factors (e.g., ambient temperature) may alter nutrient preferences and requirements revealing context specific outcomes. Herein we highlight factors that influence the energetic and nutrient demands of organisms which often times have underappreciated impacts on clarifying interventional effects on health and longevity in aging studies and subsequent translation to improve the human condition.
 
KEYWORDS:
 
carbohydrate; dietary restriction; longevity; macronutrients; protein; thermogenesis
 
xx
 
"Although typical room Ta of 20-24˚C is within the TNZ for a clothed human,
it is well below that of a mouse and is in fact a significant cold stress (Gonder & Laber,
2007; Cannon & Nedergaard, 2011). This results in a hypermetabolic state to offset the
chronic cold challenge endured by the animal, resulting in elevated food intake,
metabolic rate, heart rate, blood pressure, and circulating metabolites (e.g., blood
glucose, lipids) (Swoap et al., 2004; Overton & Williams, 2004). If a mouse living at a
thermoneutral (TN) Ta of 30˚C is transferred to the typical room temperature (RT) Ta
(22˚C), an immediate cold response is observed with increases in heat production
including shivering, food intake, heart rate, sympathetic nervous system tone, metabolic
rate, etc.(Cannon & Nedergaard, 2011). Prolonged exposure to the typical RT (22˚C) for
2 weeks or longer results in adaptive changes to meet the increased, chronic, thermal
demand (Cannon & Nedergaard, 2004). Therefore, mice in typical animal facilities show
few overt signs of cold stress unless directly compared to TN housed animals. Even
within the ILAR (Institute for Laboratory Animal Research) guidelines, a significant
increase in food intake is observed when comparing the lowest and highest
recommended Ta (19-26˚C personal observation). While this cold-induced
hypermetabolism is not unique to rodents and can be observed in humans with a large
enough cold stress (Johnson & Kark, 1947) – the chronic nature and magnitude of the
Ta exposure of mice in research facilities does not accurately reflect human exposures
in modern society. In fact, rats and mice from multiple strain backgrounds show a
reduction of caloric intake, VO2 (ml/min), mean arterial pressure and heart rate when
housed at 30˚C vs. 23˚C (Overton & Williams, 2004; Swoap et al., 2004). As discussed
above, metabolism and food intake are inversely related to Ta in mice when housed
below the TNZ. As such, a mouse housed at TN (30˚C) voluntarily reduces (~40-50%)
food intake compared with typical housing Ta (23˚C) (Overton & Williams, 2004; Swoap
et al., 2004; Cannon & Nedergaard, 2004; Cannon & Nedergaard, 2011), which is near
the maximal range of restriction normally practiced in CR/DR studies in rodents (30-
40%) (Merry, 2002; Weindruch & Walford, 1988). This raises the possibility that DR
suppresses the hypermetabolic state with elevated food intake in typical (cold) housing
conditions, returning energy intake to basal levels, and that thermoneutral housing
where energy intake is already voluntarily lowered could not be reduced a further 40-
50% without inducing malnutrition. Future studies should address this question,
particularly in light of the macronutrient requirements for long-term health and longevity
in the absence of chronic cold challenges, and the benefit (or detriment) of nutrient
restriction under basal intake conditions.
Even more to the point of macronutrient and caloric influences on lifespan,
Donhoffer and Vonotzky (1947) reported a choice experiment allowing white mice to
modulate both intake amount (calories) and preference (macronutrients) by offering
three diets with different macronutrient compositions (Donhoffer & Vonotzky, 1947).
Upon housing at typical room temperature for approximately 2-3 weeks, intake
stabilized with approximately 2/3 of calories chosen from the fat (lard) diet, with lower
amounts of protein (casein) and carbohydrate (cornstarch) diets. Lowering Ta (to 10-
11°C) resulted in an increase in caloric intake, albeit this was accounted for primarily
from additional carbohydrate consumption with protein intake remaining stable.
Furthermore, shifts from low to high Ta (29-33°C) primarily suppressed carbohydrate
intake, with again stable intake of protein and fat (Donhoffer & Vonotzky, 1947). These
intake responses are in contrast to a “no choice” scenario where lower Ta still induces
increased food intake, but proportionally across macronutrients based on the singular
diet composition (e.g., to normal ‘low fat’ chow or semi-purified rodent diets), while a
macronutrient choice scenario modulates caloric needs based on altered carbohydrate
intake (Donhoffer & Vonotzky, 1947; Leshner et al., 1971). Similar observations have
been reported with activity (exercise) preferentially modulating carbohydrate intake in
rodents (Collier et al., 1969). Considering most rodent research utilizes subthermoneutral
housing, including the GF dietary assessments related to longevity
discussed above (Solon-Biet et al., 2014), it would be important to know how
thermoneutral housing modifies the macronutrient ratio effect on health and longevity
outcomes. Similarly, the interaction of exercise or activity on macronutrient ratio
optimization could be further explored.
One example of a relatively recent gene by environment interaction in obesity
and metabolism is found in the uncoupling protein 1 (Ucp1) deletion mice. As mentioned
above, the typical housing condition in most rodent facilities requires a significant,
adaptive thermogenic response to maintain Tb. Brown adipose tissue (BAT) has been
shown to contribute to this thermogenic requirement through uncoupling metabolic
substrate utilization from ATP (adenosine triphosphate) production in the mitochondria
producing heat (i.e. a type of energy inefficiency/wasting) (Cannon & Nedergaard,
2004). Thus, it was expected the deletion of the Ucp1 gene would produce a more
“efficient” organism resulting in greater weight gain per calorie consumed. However,
early reports of Ucp1 gene knockout mice demonstrated reduced thermogenic capacity,
but with unexpected protection from diet-induced obesity (Enerback et al., 1997; Liu et
al., 2003). Follow-up studies with the same Ucp1 deletion strain performed under
housing conditions near the lower end of the TNZ (Ta 29°C) uncovered an obesogenic
phenotype of the Ucp1-/- mutant, with increased energetic efficiency (significantly
greater weight gain despite equivalent energy intake) on both low-fat and high-fat diet
protocols (Feldmann et al., 2009). In essence, correcting the thermally-induced, hypermetabolic
response by altering the Ta uncovered a metabolic phenotype in the mutant
mouse model which was expected based on the known biochemical and molecular
function, but not previously observed. How other diets with altered macronutrient
proportions might interact with this Ucp1-/- genotype and Ta for metabolic health remain
to be fully explored. The number of additional gene by environment (diet and Ta)
interactions related to metabolic health and/or longevity outcomes that are concealed in
rodent models due to standard operating procedures remains largely untested and
unknown, suggesting more research in this area may be warranted."


#217 Dean Pomerleau

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Posted 16 April 2016 - 03:15 PM

Gordo,

 

A new study looking at the "Effects of L-Citrulline Supplementation on Arterial Stiffness, Pressure Wave Reflection, and Cardiac Autonomic Responses to Acute Cold Exposure with Isometric Exercise" may indicate eating more watermelon is in order (didn't know you should eat the rinds too by the way, I will try that)...

 

It should be noted that the cardiovascular effects observed in this study are the result of acute, extreme (4 °C) cold exposure in people who aren't cold-adapted. In such people under such conditions, it's not surprising to see a rise in blood pressure, arterial stiffness and heart rate. And there is definitely an increase in heart attacks in the winter, likely attributable at least in part to an acute, cold-induced cardiovascular stress response [1][2]. Fortunately, cold acclimation and/or light exercise mitigates these sorts of cardiovascular effects [3]. From [1]:

 

In cold-adapted humans, the reduced activity of the sympathetic nervous system, in response to cold stress (due to a gradual induced decline in autonomic stimulation) may decrease the physiological perturbation during cold exposure. Furthermore, cold adaptation may mitigate cold-stress-induced changes in serum lipids and haemostatic risk factors.

 

But watermelon can't hurt either!

 

--Dean

 

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

[1] QJM. 1999 Dec;92(12):747-51.

 
Cold adaptation and the seasonal distribution of acute myocardial infarction.
 
De Lorenzo F(1), Sharma V, Scully M, Kakkar VV.
 
Author information: 
(1)Thrombosis Research Institute, London, UK. dlorenzo@tri-london.ac.uk
 
 
 
PMID: 10581338
 
---------------
[2]  Lancet. 1997 May 10;349(9062):1341-6.
 
Cold exposure and winter mortality from ischaemic heart disease, cerebrovascular 
disease, respiratory disease, and all causes in warm and cold regions of Europe. 
The Eurowinter Group.
 
[No authors listed]
 
 
BACKGROUND: Differences in baseline mortality, age structure, and influenza
epidemics confound comparisons of cold-related increases in mortality between
regions with different climates. The Eurowinter study aimed to assess whether
increases in mortality per 1 degree C fall in temperature differ in various
European regions and to relate any differences to usual winter climate and
measures to protect against cold.
METHODS: Percentage increases in deaths per day per 1 degree C fall in
temperature below 18 degrees C (indices of cold-related mortality) were estimated
by generalised linear modelling. We assessed protective factors by surveys and
adjusted by regression to 7 degrees C outdoor temperature. Cause-specific data
gathered from 1988 to 1992 were analysed by multiple regression for men and women
aged 50-59 and 65-74 in north Finland, south Finland, Baden-Württemburg, the
Netherlands, London, and north Italy (24 groups). We used a similar method to
analyse 1992 data in Athens and Palermo.
FINDINGS: The percentage increases in all-cause mortality per 1 degree C fall in 
temperature below 18 degrees C were greater in warmer regions than in colder
regions (eg, Athens 2.15% [95% CI 1.20-3.10] vs south Finland 0.27% [0.15-0.40]).
At an outdoor temperature of 7 degrees C, the mean living-room temperature was
19.2 degrees C in Athens and 21.7 degrees C in south Finland; 13% and 72% of
people in these regions, respectively, wore hats when outdoors at 7 degrees C.
Multiple regression analyses (with allowance for sex and age, in the six regions 
with full data) showed that high indices of cold-related mortality were
associated with high mean winter temperatures, low living-room temperatures,
limited bedroom heating, low proportions of people wearing hats, gloves, and
anoraks, and inactivity and shivering when outdoors at 7 degrees C (p < 0.01 for 
all-cause mortality and respiratory mortality; p > 0.05 for mortality from
ischaemic heart disease and cerebrovascular disease).
INTERPRETATION: Mortality increased to a greater extent with given fall of
temperature in regions with warm winters, in populations with cooler homes, and
among people who wore fewer clothes and were less active outdoors.
 
PMID: 9149695 
 
------------------
[3] Alaska Med. 2007;49(2 Suppl):29-31.
 
Human responses to cold.
 
Rintamäki H(1).
 
Author information: 
(1)Finnish Institute of Occupational Health, Oulu, Finland.
hannu.rintamaki@ttl.fi
 
The thermoneutral ambient temperature for naked and resting humans is ca. 27
degrees C. Exposure to cold stimulates cold receptors of the skin which causes
cold thermal sensations and stimulation of the sympathetic nervous system.
Sympathetic stimulation causes vasoconstriction in skin, arms and legs.
Diminished skin and extremity blood flow increases the thermal insulation of
superficial tissues more than 300% corresponding to 0.9 clo (0.13 degrees C x
m(-2) x W(-1)). With thermoregulatory vasoconstriction/ vasodilatation the body
heat balance can be maintained within a range of ca. 4 degrees C, the middle of
the range being at ca. 21 degrees C when light clothing is used. Below the
thermoneutral zone metabolic heat production (shivering) is stimulated and above 
the zone starts heat loss by evaporation (sweating). Cold induced
vasoconstriction increases blood pressure and viscosity and decreases plasma
volume consequently increasing cardiac work. Cold induced hypertensive response
can be counteracted by light exercise, while starting heavy work in cold markedly
increases blood pressure. Under very cold conditions the sympathetic stimulation 
opens the anastomoses between arterioles and venules which increases skin
temperatures markedly but temporarily, especially in finger tips. Adaptation to
cold takes ca. 2 weeks, whereafter the physiological responses to cold are
attenuated and cold exposure is subjectively considered less stressful.
 
PMID: 17929604

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#218 Dean Pomerleau

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Posted 16 April 2016 - 03:32 PM

Gordo,

p.s. Dean to answer your question about temp logging - I know it wouldn't be ideal, but I think just a single point plot of body temps throughout the day might be useful during CE experimentation to see what activities elicit the largest thermogenesis (TG) response.  I'm less interested in temperature deltas between various organs although that would also be useful...

 

Temperature data from a single channel would certainly be better than nothing. But I worry that changes in ambient temperature would swamp the small effects of thermogenesis on skin temperature. That is why differences in skin temperatures between a region known to be above BAT deposits vs. a region nearby but not above BAT might be a lot more useful for assessing one's thermogenic response to cold exposure.  But this would require multiple simultaneous temperature channels.

 

--Dean


There will never be peace in the world while there are animals in our bellies.

#219 TomBAvoider

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Posted 16 April 2016 - 03:38 PM

I pretty much agree with your points in your #215 post, Dean. Some small nuance, if you'll bear with me. There is true LE that works through slowing or temporarily suspending the aging process itself, and there is LE through squaring the survival curve by eliminating LE-shorteners (such as morbidity, accidents, lifestyle choices etc.). One may quibble whether the latter is true LE (since it does not in principle extend max LS). I think that while the odds of any single drug or intervention significantly affecting true LE are remote, it is evidently true that we can affect LS through lifestyle, nutrition, hygiene etc., and yes, through drugs. After all, there are drugs that successfully save lives and manage diseases. If we now think of the effects of aging as a disease state, then in principle we should be able to affect these disease states through pharmacological and other interventions (including gene therapy). 

 

To bring this home, we can ask: is there any drug that has shown true LE in mammals? I think the answer is "no" in keeping with the instinct that no single drug is likely to affect such a complex process as aging. The one *possible* exception is rapa (to date), as PMID: 19587680 indicates, although the authors of that study are somewhat equivocal as to whether the observed LE is due to slowing of the aging process or through frank disease suppression, or a combo of both. To quote from that paper:

 

"Rapamycin may extend lifespan by postponing death from cancer, by
retarding mechanisms of ageing, or both. To our knowledge, these are the first
results to demonstrate a role for mTOR signalling in the regulation of mammalian 
lifespan, as well as pharmacological extension of lifespan in both genders. These
findings have implications for further development of interventions targeting
mTOR for the treatment and prevention of age-related diseases."
 
Now, assuming the lesser of these claims, i.e. that rapa only extends LE through postponing death by suppressing cancer (or some other disease process), that still leaves open - at least in principle - the case for using pharmacological cocktails to suppress diseases of aging and bring us closer to max LS instead of dropping dead before that.
 
Obviously, a few things have to be assumed - are we even sure that there is any LE as observed by the authors of PMID: 19587680, and are we sure that's not an artifact of confounders, which seem to be horribly prevalent in almost all rodent studies, as we're reminded by Al P.'s just posted PMID: 27073168 above. This is not a trivial question - we've long known that the husbanding of rodents impacts f.ex. CR studies, but more and more we are seeing that this is a much bigger issue that encompases more variables yet (like temperature, chow composition etc.). So I think we should be cautious in simply accepting that rapa leads to LE in rodents without qualification. But assuming the best (that the answer is "yes"), we then face the dilemma you identified: what if using rapa leads to "x" time of LE, but precludes CR+CE benefits that would lead to a LE of "x+" - in which case, obviously, we would drop rapa like a hot potato and keep to CR+CE. But this is also the point at which I say we are obligated to explore the issue of using pharma interventions to augment CR/CE (my original interest in rapa) - whether it is possible, if not rapa, maybe something else or another cocktail. It is even possible that we may come up with one that displaces CR/CE and leads to greater LE. In other words, I don't think the door on pharmaceutical interventions is closed - or should be closed... after all, you must admit, Dean, that taking any supplements or indeed taking great care to consume plants that have speculative phytochemical benefits, nutraceuticals, is a form of polypharma intervention. If you are already doing that, then why not look to things like rapa, in principle? 

Edited by TomBAvoider, 16 April 2016 - 03:39 PM.


#220 Dean Pomerleau

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Posted 16 April 2016 - 04:02 PM

TomB,

 


It is even possible that we may come up with [a pharmacological intervention] that displaces CR/CE and leads to greater LE. In other words, I don't think the door on pharmaceutical interventions is closed - or should be closed... 

 

Agreed. I think we're on the same page. Recall I said:

 

[U]ntil we can eliminate the hypothesis that BAT (or thermogenesis) is important for lifespan, or show rapamycin doesn't eliminate BAT in humans, I'd consider even low-dose rapamycin a non-starter, independent of any other negative side effects it may or may not have.

 

In other words, I'm not precluding the possibility that rapamycin alone or in combination might be beneficial, in practice or in principle.

 

I'm just saying I'd need to be convinced first that it "does no harm", especially when it comes to BAT in humans, before I'd consider taking it.

 


... after all, you must admit, Dean, that taking any supplements or indeed taking great care to consume plants that have speculative phytochemical benefits, nutraceuticals, is a form of polypharma intervention. If you are already doing that, then why not look to things like rapa, in principle? 

 

I give whole plants that humans have been consumed for millennia a bit more leeway when it comes to demonstrated benefits required before I'll consider consuming them, relative to rare, isolated and powerful pharmaceutical compounds that can profoundly influence core metabolic processes (like rapamycin influences mTOR activity). It's like playing with fire. You're bound to get burned if you're not really careful.

 

But speaking of playing with fire, I've recently started experimenting with taking a capsaicin supplement to boost thermogenic activity, so to some degree I'm talking out of both sides of my mouth on this one...

 

--Dean


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Also tagged with one or more of these keywords: Cold Exposure, Exercise, Fasting, UCPs, UCP1, UCP3, FGF21