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Dean Pomerleau

Cold Exposure & Other Mild Stressors for Increased Health & Longevity

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

You know something (drug/intervention/diet) has its moment in the sun, publicly, when the hucksters and money spinners come out of the woodwork to flog their wares. I guess we can add CE to the diet, sleep and supplements schemes - grab some kernel of an idea, distort it and monetize. Same as it ever was.   

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Tom wrote:

9 hours ago, TomBAvoider said:

I guess we can add CE to the diet, sleep and supplements schemes - grab some kernel of an idea, distort it and monetize. Same as it ever was

Brown fat is certainly having its day in the sun, also most often via CE mimetics that boost BAT, like the recent "Coffee/Caffeine Boosts Brown Fat" story.

Clinton wrote:

Quote

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

I agree. One thing you, McCoy and other muscle-oriented folks might find interesting but not come across yet is the other pathway (besides brown/beige fat) that CE triggers, namely sarcolipin in skeletal muscles.

If you haven't seen the CE sarcolipin story yet, you should definitely read this introductory post, along with the follow-up posts here and here.

Recently the story about how CE -> higher muscle sarcolipin -> thermogenesis -> metabolic health has gotten a boost from this study [1], which found that elevated sarcolipin induces the creation of extra mitochondria in muscle cells, increasing the muscle cells ability to burn fat. This likely explains why previous studies (discussed in the posts above) have found that elevated sarcolipin as a result of CE or genetic manipulation results in improved fatigue resistance in muscle fibers.

Since too much fat inside muscle cells is implicated in insulin resistance, improving muscle cells' ability to oxidize fat via elevated sarcolipin may be another mechanism (besides BAT) by which cold exposure has such a positive effect on glucose metabolism.

Finally, as a bonus for you muscle hypertrophy guys, sarcolipin expression in muscle cells, which is up-regulated by both exercise and cold exposure, appears to boost calcineurin which inhibits myostatin, which together are known to increase muscle mass [2].

--Dean

----------

[1] Cell Rep. 2018 Sep 11;24(11):2919-2931. doi: 10.1016/j.celrep.2018.08.036.

Sarcolipin Signaling Promotes Mitochondrial Biogenesis and Oxidative Metabolism
in Skeletal Muscle.

Maurya SK(1), Herrera JL(1), Sahoo SK(1), Reis FCG(1), Vega RB(1), Kelly DP(2),
Periasamy M(3).

The major objective of this study was to understand the molecular basis of how

sarcolipin uncoupling of SERCA regulates muscle oxidative metabolism. Using
genetically engineered sarcolipin (SLN) mouse models and primary muscle cells, we
demonstrate that SLN plays a crucial role in mitochondrial biogenesis and
oxidative metabolism in muscle.
Loss of SLN severely compromised muscle oxidative
capacity without affecting fiber-type composition. Mice overexpressing SLN in
fast-twitch glycolytic muscle reprogrammed mitochondrial phenotype, increasing
fat utilization and protecting against high-fat diet-induced lipotoxicity. We
show that SLN affects cytosolic Ca2+ transients and activates the
Ca2+/calmodulin-dependent protein kinase II (CamKII) and PGC1α axis to increase
mitochondrial biogenesis and oxidative metabolism. These studies provide a
fundamental framework for understanding the role of sarcoplasmic reticulum
(SR)-Ca2+ cycling as an important factor in mitochondrial health and muscle
metabolism. We propose that SLN can be targeted to enhance energy expenditure in 
muscle and prevent metabolic disease.

DOI: 10.1016/j.celrep.2018.08.036 

PMID: 30208317 
 

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

[2] Am J Physiol Cell Physiol. 2017 Aug 1;313(2):C154-C161. doi:

10.1152/ajpcell.00291.2016. Epub 2017 Jun 7.

Effects of sarcolipin deletion on skeletal muscle adaptive responses to
functional overload and unload.

Fajardo VA(1), Rietze BA(1), Chambers PJ(1), Bellissimo C(1), Bombardier E(1),
Quadrilatero J(1), Tupling AR(2).

Overexpression of sarcolipin (SLN), a regulator of sarco(endo)plasmic reticulum

Ca2+-ATPases (SERCAs), stimulates calcineurin signaling to enhance skeletal
muscle oxidative capacity. Some studies have shown that calcineurin may also
control skeletal muscle mass and remodeling in response to functional overload
and unload stimuli by increasing myofiber size and the proportion of slow fibers.
To examine whether SLN might mediate these adaptive responses, we performed
soleus and gastrocnemius tenotomy in wild-type (WT) and Sln-null (Sln-/-) mice
and examined the overloaded plantaris and unloaded/tenotomized soleus muscles. In
the WT overloaded plantaris, we observed ectopic expression of SLN, myofiber
hypertrophy, increased fiber number, and a fast-to-slow fiber type shift, which
were associated with increased calcineurin signaling (NFAT dephosphorylation and 
increased stabilin-2 protein content) and reduced SERCA activity. In the WT
tenotomized soleus, we observed a 14-fold increase in SLN protein, myofiber
atrophy, decreased fiber number, and a slow-to-fast fiber type shift, which were 
also associated with increased calcineurin signaling and reduced SERCA activity. 
Genetic deletion of Sln altered these physiological outcomes, with the overloaded
plantaris myofibers failing to grow in size and number, and transition towards
the slow fiber type, while the unloaded soleus muscles exhibited greater
reductions in fiber size and number, and an accelerated slow-to-fast fiber type
shift. In both the Sln-/- overloaded and unloaded muscles, these findings were
associated with elevated SERCA activity and blunted calcineurin signaling. Thus, 
SLN plays an important role in adaptive muscle remodeling potentially through
calcineurin stimulation, which could have important implications for other muscle
diseases and conditions.

Copyright © 2017 the American Physiological Society.

DOI: 10.1152/ajpcell.00291.2016 
PMID: 28592414  [Indexed for MEDLINE]
 

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Thanks to Dean for the informative posts. Here is another interesting overview on the subject, including an evolutionary perspective:

"Reviews on whole body human cold adaptation generally do not distinguish between population studies and dedicated acclimation studies, leading to confusing results. Population studies show that indigenous black Africans have reduced shivering thermogenesis in the cold and poor cold induced vasodilation in fingers and toes compared to Caucasians and Inuit. About 40,000 y after humans left Africa, natives in cold terrestrial areas seems to have developed not only behavioral adaptations, but also physiological adaptations to cold. Dedicated studies show that repeated whole body exposure of individual volunteers, mainly Caucasians, to severe cold results in reduced cold sensation but no major physiological changes. Repeated cold water immersion seems to slightly reduce metabolic heat production, while repeated exposure to milder cold conditions shows some increase in metabolic heat production, in particular non-shivering thermogenesis. In conclusion, human cold adaptation in the form of increased metabolism and insulation seems to have occurred during recent evolution in populations, but cannot be developed during a lifetime in cold conditions as encountered in temperate and arctic regions. Therefore, we mainly depend on our behavioral skills to live in and survive the cold."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4861193/

See also :https://royalsocietypublishing.org/doi/full/10.1098/rspb.2009.0752

Still, nothing I see strikes me as compelling evidence that cold exposure over the long term correlates with longevity. It appears that while cold exposure has some beneficial short term effects, there are also negative effects and overall, there is no evidence that it positively impacts longevity. Mind you, heat exposure has beneficial short term effects, based on studies I've seen.

But the bottom line is, we see population-wide evidence that humans who 
exercise, who eat low protein and plant-based diet, who don't smoke or drink excessively and who practice CR (traditionally, largely because of limited access to calories), generally live longer than populations which do not. But the longevity of Inuits is about the same as the longevity of Bushmen, despite the dramatically different temperatures of their native environments.

While BMR is not necessarily correlated with longevity in all species, in humans it appears to be. Native populations living in cold climates appear to have higher BMR on average.

See this, for example (it's sort of on point):

"Despite longstanding controversies from animal studies on the relationship between basal metabolic rate (BMR) and longevity, whether BMR is a risk factor for mortality has never been tested in humans. We evaluate the longitudinal changes in BMR and the relationship between BMR and mortality in the Baltimore Longitudinal Study of Aging (BLSA) participants.

Methods

BMR and medical information were collected at the study entry and approximately every 2 years in 1227 participants (972 men) over a 40-year follow-up. BMR, expressed as kcal/m2/h, was estimated from the basal O2 consumption and CO2 production measured by open-circuit method. Data on all-cause and specific-cause mortality were also obtained.

Result

BMR declined with age at a rate that accelerated at older ages. Independent of age, participants who died had a higher BMR compared to those who survived. BMR was a significant risk factor for mortality independent of secular trends in mortality and other well-recognized risk factors for mortality, such as age, body mass index, smoking, white blood cell count, and diabetes. BMR was nonlinearly associated with mortality. The lowest mortality rate was found in the BMR range 31.3–33.9 kcal/m2/h. Participants with BMR in the range 33.9–36.4 kcal/m2/h and above the threshold of 36.4 kcal/m2/h experienced 28% (hazard ratio: 1.28; 95% confidence interval, 1.02–1.61) and 53% (hazard ratio: 1.53; 95% confidence interval, 1.19–1.96) higher mortality risk compared to participants with BMR 31.3–33.9 kcal/m2/h.

Conclusion

We confirm previous findings of an age-related decline of BMR. In our study, a blunted age-related decline in BMR was associated with higher mortality, suggesting that such condition reflects poor health status."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4984846/

Edited by Ron Put

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Dean, I'm curious your thoughts on this  -(referenced above): https://www.longecity.org/forum/topic/102741-an-ancient-heat-shocknrf2pluripotency-related-epigenetic-turn-accelerates-human-aging-and-these-can-be-modulated/ ?  I hope I did not offend with the comparison to your well-documented hypothesis at the opposite end of the ambient temperature range.

For CE, thought this recent review would interest you:   https://www.ncbi.nlm.nih.gov/pubmed/31230192 ( ComBATing aging-does increased brown adipose tissue activity confer longevity?)

--- we've come a long way since (Mattson, 2009): https://www.sciencedirect.com/science/article/pii/S1568163709000804 (Perspective: Does brown fat protect against diseases of aging?)

 

Edited by Mechanism

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Ron wrote:

18 hours ago, Ron Put said:

Still nothing I see strikes me as compelling evidence that cold exposure over the long term correlates with longevity.

Sigh... Except that I've shown you here that living in a colder climate does correlated positively with longer lifespan in a study of nearly 100 different species whose habitats range over many different latitudes.

And I've explained to you repeatedly why you shouldn't expect to see it in humans for a variety of reasons (see here).

18 hours ago, Ron Put said:

But the longevity of Inuits is about the same as the longevity of Bushmen, despite the dramatically different temperatures of their native environments.

OMG. I can't believe you actually said that. First of all, your wrong and you clearly didn't even bother to check. In fact, the Inuit do live dramatically longer than Bushman. From this study of Bushman of the Kalahari:

"Average life expectancy is about 45-50 years; respiratory infections and malaria are the major reasons for death in adults. Only 10% become older than 60 years."

While the Inuit on the other hand have an average life expectancy around 70. From here:

"[Between 1998 and 2008] Male [Inuit] life expectancy rose to 67.7 years from 63.5 years; among women, life expectancy rose to 72.8 years from 71.1 years."

So on average, the cold-exposed Inuit live about 20 years longer than much warmer Bushman.

In truth, this says absolutely nothing about the cold-exposure hypothesis I'm arguing for, but by your (faulty) logic, it should provide compelling evidence to change your mind and endorse CE. Of course I'm not holding my breath given your track record...

18 hours ago, Ron Put said:

It appears that while cold exposure has some beneficial short term effects,

You've alluded to "short term" benefits of CE before. I challenged you there and I challenge you again to provide actual evidence to back of the idea of diminishing benefits of CE over time (e.g. on glucose metabolic). So far you have just expressing your (misguided) opinion, as far as I can tell.

18 hours ago, Ron Put said:

there are also negative effects

Which you've alluded to before, and I addressed here (short answer, start CE slow and avoid acute cold exposure if you are at risk of a heart attack).

Quote

While BMR is not necessarily correlated with longevity in all species, in humans it appears to be.

BMR is correlated with longevity in most mammalian species (including humans), but in not in the way that you think. Higher BMR is associated with longer lifespan. Ironically, the study you cite [1], actually shows this if you'd have bothered to actually read it. See below for discussion of [1] and other studies that show higher BMR is associated with improved longevity in humans and other animals.

18 hours ago, Ron Put said:

Native populations living in cold climates appear to have higher BMR on average.

You are probably right. And as we saw above by your own example, the higher-BMR natives of the far north (Inuit) live substantially longer than warmer natives of the African savanna (Bushman). Again, I don't consider this credible evidence. But you appear to, and so are effectively refuted your own argument. 

18 hours ago, Ron Put said:

See this [1], for example (it's sort of on point):

Oh boy. No it's not on point, at least in the way that you think it is. And I sense that at some level you realize that, based on your "sort of" qualification. In fact, while it doesn't seem possible, this study is actually even worse for your argument than your "Inuit vs. Bushman" comparison. Let me explain.

You are referring to study [1], which followed 1227 people (mostly men) from Baltimore for 40 years, with follow-ups ever 2 years, including repeated measurements of their the basal metabolic rate.

First of all, right from the abstract, the authors observed:

"BMR declined with age at a rate that accelerated at older ages." 

You know what else declines with age? Levels of BAT and the ability to thermoregulate. You know what else increases with age, and that increases at an accelerating rate at older ages? Risk of death. Putting the three together, falling BAT is correlated with declining BMR which in turn correlates with increased mortality. See a pattern? But of course, correlation is not causation.

Next, the authors explicitly suggest in the abstract why this study is completely irrelevant with respect to the cold exposure hypothesis. They say:

"In our study, a blunted age-related decline in BMR was associated with higher mortality, suggesting that such condition reflects poor health status." 

If you had bothered to read it, the full text elaborates on the connection between poor health / disease and increased BMR. They say:

"The discrepancy in BMR between individuals who died and those who survived may indicate pathological conditions causing a homeostatic dysregulation that substantially increase minimum energy requirements."

In other words, these people didn't have a higher metabolic rate because of cold exposure,  but likely because they had diseases or other metabolic dysfunction that cause a higher BMR, and an increased likelihood of death.

In another paper by the same authors [2], they suggest that the increased mortality among high-BMR elderly may be the result of "chronic heart failure, cancer" or "higher circulating levels of tumor necrosis factor and other proinflammatory cytokines," all of which have been shown to increase BMR, all of which are bad for health/longevity and none of which have anything to do with the topic at hand, cold exposure, except in an inverse way - i. e. CE results in lower levels of inflammation and cancer. 

Your argument is like saying "smoking increases BMR, and smoking increases mortality, so cold exposure is likely to be bad for you since it too increases BMR."

But remarkably, it gets even worse for your contention that this study refutes the cold exposure hypothesis.

Again if you'd bothered to read the full text of your study [1], you'd have seen from the first line of Table 1 (reproduced below), that having at higher metabolic rate at the start of the study was strongly correlated with increased survival over the subsequent ~40 years in both men (p < 0.0001) and women (p < 0.05):

EahTDAT.jpg

So much for the idea that low BMR is good. By the way, this evidence that higher baseline BMR is associate with increased longevity in (healthy) humans is quite in line with evidence from rodents [3], birds [4], and dogs [5]. 

And note from the two other highlighted rows, the rate of smoking at the start of the study among those higher-BMR subjects who would survive was nearly identical to (but actually a little lower than) those who subsequently died during follow-up (p > 0.05). For example, at the start of the study 36.1% of survivor men were never smokers, while 37.2% of men who would later die during the study were never smokers - not much different. So the BMR difference at the start of the study between survivors and those who later died had nothing to do with smoking rates. 

Why am I highlighting the smoking rates at study onset? Because here is the real kicker that (further) obliterates the idea that this study provides evidence that "higher BMR is bad, so cold exposure is likely to be bad too."

Take a look at Table 5 from [1], with particular attention on the last two highlighted lines:

uYfg6st.jpg

 

Notice anything troubling? The "current smokers" line represents the fraction of the time individuals in each of the four BMR categories reported being a "current smoker" every 2 years during the 40 year followup. As you can see, the rate of smoking was very strongly correlated with BMR (p < 0.0001). In fact, the participants with the highest metabolic rate were more than 3 times more likely to report being a smoker at each time point during the follow-up period (43% vs. 14%). 

So it is no wonder that those with the higher BMR were more likely to die during follow-up. Its clear that those study participates who decided to pick up a smoking habit (or not quit) during the follow-up period had a higher BMR (which smoking will do to you), and were more likely to die (which smoking will also do to you).

In short, your study [1] with supposed "evidence" against having a higher than average metabolic rate (and therefore against cold exposure) is really saying that having a higher BMR as a results of underlying disease, metabolic dysfunction and/or smoking is bad for longevity. Obviously this is completely irrelevant to the effects of CE on metabolic rate and longevity.

While otherwise pretty worthless as evidence, your study [1] was interesting if only because it also showed that having a higher BMR at baseline (when participants were healthy and their smoking rates were the same across categories) was positively correlated with long-term survival. Of course this evidence from people, along with the evidence from other species cited above that higher BMR is associated with better survival seems to fly in the face of your speculation that having a higher metabolic rate is bad for longevity, so CE will likely be bad (or at least not helpful) for longevity too. 

--Dean

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

[1] J Gerontol A Biol Sci Med Sci. 2008 Jul;63(7):698-706.

High basal metabolic rate is a risk factor for mortality: the Baltimore
Longitudinal Study of Aging.

Ruggiero C(1), Metter EJ, Melenovsky V, Cherubini A, Najjar SS, Ble A, Senin U,
Longo DL, Ferrucci L.

Author information: 
(1)National Institute on Aging, NIH, Harbor Hospital, Baltimore, MD 21225, USA.
ruggieroc07@hotmail.it

BACKGROUND: Despite longstanding controversies from animal studies on the
relationship between basal metabolic rate (BMR) and longevity, whether BMR is a
risk factor for mortality has never been tested in humans. We evaluate the
longitudinal changes in BMR and the relationship between BMR and mortality in the
Baltimore Longitudinal Study of Aging (BLSA) participants.
METHODS: BMR and medical information were collected at the study entry and
approximately every 2 years in 1227 participants (972 men) over a 40-year
follow-up. BMR, expressed as kcal/m(2)/h, was estimated from the basal O(2)
consumption and CO(2) production measured by open-circuit method. Data on
all-cause and specific-cause mortality were also obtained.
RESULT: BMR declined with age at a rate that accelerated at older ages.
Independent of age, participants who died had a higher BMR compared to those who 
survived. BMR was a significant risk factor for mortality independent of secular 
trends in mortality and other well-recognized risk factors for mortality, such as
age, body mass index, smoking, white blood cell count, and diabetes. BMR was
nonlinearly associated with mortality. The lowest mortality rate was found in the
BMR range 31.3-33.9 kcal/m(2)/h. Participants with BMR in the range 33.9-36.4
kcal/m(2)/h and above the threshold of 36.4 kcal/m(2)/h experienced 28% (hazard
ratio: 1.28; 95% confidence interval, 1.02-1.61) and 53% (hazard ratio: 1.53; 95%
confidence interval, 1.19-1.96) higher mortality risk compared to participants
with BMR 31.3-33.9 kcal/m(2)/h.
CONCLUSION: We confirm previous findings of an age-related decline of BMR. In our
study, a blunted age-related decline in BMR was associated with higher mortality,
suggesting that such condition reflects poor health status.

DOI: 10.1093/gerona/63.7.698 
PMCID: PMC4984846
PMID: 18693224  [Indexed for MEDLINE]
 

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

[2] J Gerontol A Biol Sci Med Sci. 2006 May;61(5):466-71.

The endeavor of high maintenance homeostasis: resting metabolic rate and the
legacy of longevity.

Ruggiero C, Ferrucci L.

Metabolism, the continuous conversion between structural molecules and energy, is
life in essence. Size, metabolic rate, and maximum life span appear to be
inextricably interconnected in all biological organisms and almost follow a
"universal" law. The notion of metabolic rate as the natural "rate of living"
filled most of the academic discussion on aging in the early 20th century to be
later replaced by the free-radical theory of aging. We argue that the rate of
living theory was discarded too quickly and that studying factors affecting
resting metabolic rate during the aging process may provide great insight into
the core mechanisms explaining differential longevity between individuals, and
possibly the process leading to frailty. We predict that measures of resting
metabolic rate will be introduced in geriatric clinical practice to gather
information on the degree of multisystem dysregulation, exhaustion of energy
reserve, and risk of irreversible frailty.

DOI: 10.1093/gerona/61.5.466 
PMCID: PMC2645618
PMID: 16720742  [Indexed for MEDLINE]
 

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

[3] Aging Cell. 2004 Jun;3(3):87-95.

Uncoupled and surviving: individual mice with high metabolism have greater
mitochondrial uncoupling and live longer.

Speakman JR(1), Talbot DA, Selman C, Snart S, McLaren JS, Redman P, Krol E,
Jackson DM, Johnson MS, Brand MD.

Author information: 
(1)Aberdeen Centre for Energy Regulation and Obesity (ACERO), School of
Biological Sciences, University of Aberdeen, Aberdeen, Scotland, UK AB24 2TZ.
j.Speakman@abdn.ac.uk

Two theories of how energy metabolism should be associated with longevity, both
mediated via free-radical production, make completely contrary predictions. The
'rate of living-free-radical theory' (Pearl, 1928; Harman, 1956; Sohal, 2002)
suggests a negative association, the 'uncoupling to survive' hypothesis (Brand,
2000) suggests the correlation should be positive. Existing empirical data on
this issue is contradictory and extremely confused (Rubner, 1908; Yan & Sohal,
2000; Ragland & Sohal, 1975; Daan et al., 1996; Wolf & Schmid-Hempel, 1989]. We
sought associations between longevity and individual variations in energy
metabolism in a cohort of outbred mice. We found a positive association between
metabolic intensity (kJ daily food assimilation expressed as g/body mass) and
lifespan, but no relationships of lifespan to body mass, fat mass or lean body
mass. Mice in the upper quartile of metabolic intensities had greater resting
oxygen consumption by 17% and lived 36% longer than mice in the lowest intensity 
quartile. Mitochondria isolated from the skeletal muscle of mice in the upper
quartile had higher proton conductance than mitochondria from mice from the
lowest quartile. The higher conductance was caused by higher levels of endogenous
activators of proton leak through the adenine nucleotide translocase and
uncoupling protein-3. Individuals with high metabolism were therefore more
uncoupled, had greater resting and total daily energy expenditures and survived
longest - supporting the 'uncoupling to survive' hypothesis.

Copyright 2004 Blackwell Publishing Ltd.

DOI: 10.1111/j.1474-9728.2004.00097.x 
PMID: 15153176  [Indexed for MEDLINE]

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

[4] Age (Dordr). 2008 Sep;30(2-3):75-87. doi: 10.1007/s11357-008-9054-3. Epub 2008

Jun 25.

Energetics and longevity in birds.

Furness LJ(1), Speakman JR.

Author information: 
(1)Institute of Biological and Environmental Sciences, University of Aberdeen,
Aberdeen, AB24 2TZ, Scotland, UK.

The links between energy expenditure and ageing are different at different levels
of enquiry. When studies have examined the relationships between different
species within a given class the association is generally negative--animals with 
greater metabolism per gram of tissue live shorter lives. Within species, or
between classes (e.g. between birds and mammals) the association is the
opposite--animals with higher metabolic rates live longer. We have previously
shown in mammals that the negative association between lifespan and metabolic
rate is in fact an artefact of using resting rather than daily energy
expenditure
, and of failing to adequately take into account the confounding
effects of body size and the lack of phylogenetic independence of species data.
When these factors are accounted for, across species of mammals, the ones with
higher metabolism also have the largest lifetime expenditures of
energy-consistent with the inter-class and intra-specific data. A previous
analysis in birds did not yield the same pattern, but this may have been due to a
lack of sufficient power in the analysis. Here we present an analysis of a much
enlarged data set (>300 species) for metabolic and longevity traits in birds.
These data show very similar patterns to those in mammals. Larger individuals
have longer lives and lower per-gram resting and daily energy expenditures, hence
there is a strong negative relationship between longevity and mass-specific
metabolism. This relationship disappears when the confounding effects of body
mass and phylogeny are accounted for. Across species of birds, lifetime
expenditure of energy per gram of tissue based on both daily and resting energy
expenditure is positively related to metabolic intensity, mirroring these
statistical relationships in mammals and synergizing with the positive
associations of metabolism with lifespan within species and between vertebrate
classes.

DOI: 10.1007/s11357-008-9054-3 
PMCID: PMC2527636
PMID: 19424858 
 

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

[5] 

1. Aging Cell. 2003 Oct;2(5):265-75.

Age-related changes in the metabolism and body composition of three dog breeds
and their relationship to life expectancy.

Speakman JR(1), van Acker A, Harper EJ.

Author information: 
(1)Aberdeen Centre for Energy Regulation and Obesity, School of Biological
Sciences, Zoology Building, University of Aberdeen, Aberdeen AB24 2TZ, Scotland, 
UK. j.speakman@abdn.ac.uk

We measured body composition and resting metabolic rates (RMR) of three dog
breeds (Papillons, mean body mass 3.0 kg (n = 35), Labrador retrievers, mean body
mass 29.8 kg (n = 35) and Great Danes, mean body mass 62.8 kg (n = 35)) that
varied between 0.6 and 14.3 years of age. In Papillons, lean body mass (LBM)
increased with age but fat mass (FBM) was constant; in Labradors, both LBM and
FBM were constant with age, and in Great Danes, FBM increased with age but LBM
was constant. FBM averaged 14.8% and 15.7% of body mass in Papillons and
Labradors, respectively. Great Danes were leaner and averaged only 10.5% FBM.
Pooling the data for all individuals, the RMR was significantly and positively
associated with LBM and FBM and negatively associated with age. Once these
factors had been taken into account there was still a significant breed effect on
RMR, which was significantly lower in Labradors than in the other two breeds.
Using the predictive multiple regression equation for RMR and the temporal trends
in body composition, we modelled the expenditure of energy (at rest) over the
first 8 years of life, and over the entire lifespan for each breed. Over the
first 8 years of life the average expenditure of energy per kg LBM were 0.985,
0.675 and 0.662 GJ for Papillons, Labradors and Great Danes, respectively. This
energy expenditure was almost 60% greater for the smallest compared with the
largest breed. On average, however, the life expectancy for the smallest breed
was a further 6 years (i.e. 14 years in total), whereas for the largest breed it 
was only another 6 months (i.e. 8.5 years in total). Total lifetime expenditure
of energy at rest per kg LBM averaged 1.584, 0.918 and 0.691 GJ for Papillons,
Labradors and Great Danes, respectively. In Labradors, total daily energy
expenditure, measured by the doubly labelled water method in eight animals, was
only 16% greater than the observed RMR. High energy expenditure in dogs appears
positively linked to increased life expectancy,
contrary to the finding across
mammal species and within exotherms, yet resembling observations in other
intra-specific studies. These contrasting correlations suggest that metabolism is
affecting life expectancy in different ways at these different levels of enquiry.

DOI: 10.1046/j.1474-9728.2003.00061.x 
PMID: 14570234  [Indexed for MEDLINE]
 

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19 hours ago, Mechanism said:

Mechanism,

I haven't looked at the evidence in favor of brief exposure to extreme heat (e.g. saunas) in a while. Last I checked there was pretty good evidence to support the health benefits of brief heat exposure, mostly mediated by increased expression of heat shock proteins which protect against DNA damage caused by heat and other stressors.

Fortunately, cold exposure also upregulate heat shock proteins, including arguably the most important one (hsp70), as I discuss in the benefits section of the Cold Exposure Albatross post.

Since cold exposure upregulates many of the same heat shock proteins and since prolonged exposure to warm conditions reduces BAT, not to mention counteracts the benefits of CR, I haven't investigated or pursued heat exposure further. 

If you see good evidence that brief exposure to high heat has benefits over and above cold exposure, and won't undermine the well documented benefits of CE (or CR), please feel free to share them here.

--Dean

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Ames Dwarf Mice Have More BAT and Warm Housing Ruins Its Beneficial Effects

Ames dwarf mice are quite interesting when it comes to longevity and metabolism. Most significantly, they live up to 60% longer than normal mice. They also exhibit hypothyroidism and low body temperature when housed at normal (chilly for mice) room temperature. At first blush, this might look like evidence against the CE hypothesis (i.e. the idea that cold exposure and BAT is good for health and longevity), since low body temperature might suggest that Ames mice don't have much BAT to keep them warm through thermogenesis. 

Yet paradoxically, they also burn more calories per gram of body weight than normal mice (further debunking the idea that a high BMR is bad for you).

To find out what gives with these long-lived Ames mice, in 2016 Darcy et al. investigated the BAT metabolism of Ames mice both at normal room temperature [1] and more recently (2018) at thermoneutrality (30C or 80F) [2].

What they found was quite remarkable, and amazingly well-aligned with the CE hypothesis.

What they found in [1] was that rather than having less (and less active) BAT, Ames dwarf mice have more (and more active) BAT when housed at normal room temperature than normal mice. Furthermore, when they surgically removed the BAT from the two groups of mice, the Ames mice were much better than normal mice at converting white adipose tissue to metabolically active beige adipose tissue. 

Here is a juicy quote from [1] regarding glucose metabolism and insulin sensitivity in Ames mice:

It is believed that improved insulin sensitivity and energy metabolism are key mechanisms of the extended longevity of Ames dwarf mice (10). Because BAT plays a major role in energy metabolism (8) and has been shown to play a role in glucose homeostasis (22), we hypothesized that BAT may be important in the improved energy metabolism and insulin sensitivity in Ames dwarf mice. [my emphasis].

They didn't see impairment in glucose metabolism or insulin sensitivity in the BAT-ablated Ames mice, although there was a trend towards insulin resistance in the BAT-less Ames mice. Getting rid of their BAT may have had little negative effect on their metabolic health because the BAT-less Ames mice were able to convert their WAT to "beige fat" to burn glucose and fat and thereby maintain their metabolic health (see discussion of [2] below for more evidence of this).

But before we get to [2], a couple more nice quotes from [1]. In alignment with my hypothesis that it is the elevated level of norepinephrine as a result of cold exposure that starts the chain of benefits, they say the following:

In rodents, BAT thermogenesis begins with [norepinephrine - NE] binding to [the beta3 adrenegeric receptor] (8). Because of this, a NE challenge can be used to measure sympathetic outflow (19, 23). As measured by both VO2 and heat production after a NE challenge, Ames dwarf mice have a more robust sympathetic outflow compared with their normal littermates. Interestingly, iBAT removal did not significantly alter sympathetic outflow, although a numerical decrease was observed in the dwarf mice.

And they observe this bit of gold for the CE hypothesis:

By increasing the amount of BAT and expression of genes related to thermogenesis, Ames dwarf mice are able to improve their energy metabolism, which we believe to be a key regulator of their extended longevity because improved energy metabolism in Ames dwarf mice is associated with lower reactive oxygen species production and maintenance of mitochondrial DNA (33,–36) and favorable alterations in the activity of electron transport chain complexes (37, 38), which are all associated with increased longevity (39). Moreover, phosphatase and tensin homolog transgenic mice have hyperactive BAT and are long lived (40), and mice with increased uncoupling in skeletal muscle due to increased UCP-1 have a delay in aging and age-related diseases (41). Furthermore, increased uncoupling appears to affect longevity in humans as well (42, 43).

I plan to do one or more posts soon on this goldmine of studies [40-43]. Stay tuned.

Now I realize this post has gotten so long, I should break it into two parts. In the next part, I'll discuss [2], which investigates how Ames dwarf mice response when housed at thermoneutrality rather than (chilly-for-mice) room temperature.

--Dean

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

[1] Endocrinology. 2016 Dec;157(12):4744-4753. Epub 2016 Oct 14.

Brown Adipose Tissue Function Is Enhanced in Long-Lived, Male Ames Dwarf Mice.

Darcy J(1), McFadden S(1), Fang Y(1), Huber JA(1), Zhang C(1), Sun LY(1), Bartke 
A(1).

Ames dwarf mice (Prop1df/df) are long-lived due to a loss of function mutation,

resulting in deficiency of GH, TSH, and prolactin. Along with a marked extension 
of longevity, Ames dwarf mice have improved energy metabolism as measured by an
increase in their oxygen consumption and heat production, as well as a decrease
in their respiratory quotient. Along with alterations in energy metabolism, Ames 
dwarf mice have a lower core body temperature. Moreover, Ames dwarf mice have
functionally altered epididymal white adipose tissue (WAT) that improves, rather 
than impairs, their insulin sensitivity due to a shift from pro- to
anti-inflammatory cytokine secretion. Given the unique phenotype of Ames dwarf
epididymal WAT, their improved energy metabolism, and lower core body
temperature, we hypothesized that Ames dwarf brown adipose tissue (BAT) may
function differently from that of their normal littermates. Here we use histology
and RT-PCR to demonstrate that Ames dwarf mice have enhanced BAT function. We
also use interscapular BAT removal to demonstrate that BAT is necessary for Ames 
dwarf energy metabolism and thermogenesis, whereas it is less important for their
normal littermates. Furthermore, we show that Ames dwarf mice are able to
compensate for loss of interscapular BAT by using their WAT depots as an energy
source. These findings demonstrate enhanced BAT function in animals with GH and
thyroid hormone deficiencies, chronic reduction of body temperature, and
remarkably extended longevity.

DOI: 10.1210/en.2016-1593 
PMCID: PMC5133358
PMID: 27740871  [Indexed for MEDLINE]
 

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I haven't seen a scholarly smack down like that in a while, pwnd.

I'm glad to see this thread getting new life.  Along those lines, one of the more interesting search results that caught my eye was the just published (July 1, 2019):

Cordycepin regulates body weight by inhibiting lipid droplet formation, promoting lipolysis and recruiting beige adipocytes.

https://www.ncbi.nlm.nih.gov/pubmed/31259423

Most important finding of the study: 

RESULTS: We found that cordycepin could promote the transformation of white adipocytes into beige and brown adipocytes. 

This goes along with the observation that so many foods associated with great health and longevity are somehow associated with BAT.  Cordycepin is found in the Cordyceps mushroom, long revered for being associated with good health and long life:  https://www2.bing.com/search?q=Cordyceps+longevity&FORM=HDRSC1

(below is just a screen shot of the top results returned from a web search on cordyceps)

image.png.1148d74455e9b45d2ed6f58b60451852.png

image.thumb.png.4c1438be7f77d35758b790b8779bee33.png

Edited by Gordo

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Gordo wrote (quoting [1]):

Quote

RESULTS: We found that cordycepin could promote the transformation of white adipocytes into beige and brown adipocytes.

Wow Gordo, that's interesting! I can't believe I never bothered to check if any fungi are BAT boosters. Sadly, while Shitake mushrooms appear to improve metabolic health and reduce white fat mass [2], from the full text it doesn't appear to be BAT-related, since weight of BAT wasn't increased in mice fed a diet supplemented with Shitake.

I've updated the list.

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

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

--Dean

---------

[1] J Pharm Pharmacol. 2019 Jul 1. doi: 10.1111/jphp.13127. [Epub ahead of print]

Cordycepin regulates body weight by inhibiting lipid droplet formation, promoting
lipolysis and recruiting beige adipocytes.

Xu H(1), Wu B(1), Wang X(2), Ma F(1), Li Y(1), An Y(1), Wang C(1), Wang X(1),
Luan W(1), Li S(1), Liu M(1)(3), Xu J(4), Wang H(4), Tang X(2), Yu L(1).

OBJECTIVE: To explore the effect of cordycepin on reducing lipid droplets in

adipocytes.
METHODS: Rats were fed a 60% high-fat diet to construct a hyperlipidaemia animal 
model and then treated with cordycepin at different concentrations for 8 weeks.
Adipocytes were extracted, and BODIPY staining was used to detect the size of the
lipid droplets. The adipocyte membrane proteins ASC-1, PAT2 and P2RX5 were
assessed to determine the transformation of white adipocytes to beige and brown
adipocytes. In an in vitro study, 3T3-L1 cells were cultured, and Western
blotting was used to determine the expression of the lipid droplet-related genes 
Fsp27, perilipin 3, perilipin 2, PPAR-γ, Rab5, Rab7, Rab11, perilipin 1, ATGL and
CGI-58.
RESULTS: We found that cordycepin could promote the transformation of white
adipocytes into beige and brown adipocytes.
Cordycepin also downregulated the
lipid droplet-associated genes Fsp27, perilipin 3, perilipin 2, Rab5, Rab11 and
perilipin 1. Moreover, cordycepin reduced the expression of protein CGI-58, which
inhibits lipid droplet degradation. In addition, cordycepin significantly
increased the expression of ATGL, suggesting that cordycepin might stimulate
lipolysis by upregulating the expression of ATGL instead of CGI-58 and by
downregulating the expression of perilipin 1.
CONCLUSIONS: Cordycepin could blockade lipid droplet formation and promote lipid 
droplet degradation.

© 2019 Royal Pharmaceutical Society.

DOI: 10.1111/jphp.13127 
PMID: 31259423 

--------

[2] J Obes. 2011;2011:258051. doi: 10.1155/2011/258051. Epub 2011 Oct 19.

Dietary Shiitake Mushroom (Lentinus edodes) Prevents Fat Deposition and Lowers
Triglyceride in Rats Fed a High-Fat Diet.

Handayani D(1), Chen J, Meyer BJ, Huang XF.

Author information: 
(1)Metabolic Research Centre, School of Health Sciences and Illawarra Health and 
Medical Research Institute, University of Wollongong, Wollongong, NSW 2522,
Australia.

High-fat diet (HFD) induces obesity. This study examined the effects of Shiitake 
mushroom on the prevention of alterations of plasma lipid profiles, fat
deposition, energy efficiency, and body fat index induced by HFD. Rats were given
a low, medium, and high (7, 20, 60 g/kg = LD-M, MD-M, HD-M) Shiitake mushroom
powder in their high-fat (50% in kcal) diets for 6 weeks. The results showed that
the rats on the HD-M diet had the lowest body weight gain compared to MD-M and
LD-M groups (P < 0.05). The total fat deposition was significantly lower (-35%, P
< 0.05) in rats fed an HD-M diet than that of HFD group. Interestingly, plasma
triacylglycerol (TAG) level was significantly lower (-55%, P < 0.05) in rats on
HD-M than HFD. This study also revealed the existence of negative correlations
between the amount of Shiitake mushroom supplementation and body weight gain,
plasma TAG, and total fat masses.

DOI: 10.1155/2011/258051 
PMCID: PMC3199106
PMID: 22028957 
 

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Ames Dwarf Mice Have More BAT and Warm Housing Ruins Its Beneficial Effects [Pt. 2]

In part 1 of this post above, we saw from [1] that long-lived Ames dwarf mice have more (and more active) BAT at normal room temperature. Plus, when you surgically remove their BAT, they convert white fat to brown/beige fat, thereby helping them maintain their superb metabolic health. The authors of [1] speculated that increased BAT activity and thermogenesis, and the concomitant improvement in glucose metabolism and insulin sensitivity may be the mechanism by which Ames dwarf mice achieve their remarkable longevity advantage relative to normal mice.

That was in 2016. Last year the same authors did a study [2] to see what happens to Ames dwarf and normal mice when you house them at thermoneutrality (80F/30C) rather than chilly-for-mice room temperature (72F/20C).

They found exactly what you'd expect metabolically. A warmer housing temperature diminished the Ames mice's BAT activity to the point of being indistinguishable from normal mice, and almost entirely erased the large glucose metabolism advantage that cool-housed Ames mice exhibit relative to normal mice, an advantage that the authors believe to be "a key regulator of their extended longevity."

Interestingly, one of the same authors from [1] and [2] (Bartke) found basically the same results in a different, long-lived mutant mice - GHR-knockout mice [3]. Specifically, like the Ames mice, they are small in size due to a lack of growth-hormone signaling, but have a much higher metabolic rate than normal mice at room temperature. Similarly to the Ames mice, housing the GH-knockout mice at thermoneutral temperature eliminates the difference in metabolic rate relative to normal mice. Like the conclusion in [1], the authors of [3] say:

"We suspected that the increase of VO2 in GH-related mutants could reflect increased energy expenditure for thermogenesis needed to compensate for increased heat loss. Increased radiation of heat would be expected in these diminutive animals because of the increased body surface to mass ratio. To test the validity of this explanation, we have compared VO2 in GHR-KO and normal mice at a thermoneutral ambient temperature of 30°C. Under these conditions, VO2 of the mutants greatly declined from the values measured at lower temperature and no longer differed from the normal animals (Westbrook et al., unpublished). We conclude that increased VO2 in long-lived dwarf mice reflects increased energy demand for thermogenesis under conditions imposed by housing at the standard animal room ambient temperature (approximately 22°C). It is an intriguing possibility that this increase in energy expenditure might contribute to slow aging and extended longevity of these mutants.
And more succinctly:
"We suspect that increased oxidative metabolism combined with enhanced fatty acid oxidation contribute to the extended longevity of GHR-KO mice."

In short, all this evidence suggests that the superstars of rodent longevity may owe their remarkable lifespan at least in part to the metabolic improvements resulting from having more BAT and engaging in more thermogenesis when housed at (cool-for-mice) room temperature. 

Unfortunately I have seen anyone report on the logical next experiment with either of these long-lived dwarf mice. Namely to house them at thermoneutrality for their entire life to see if living in warmth erases their longevity advantage. I strongly suspect it would/will, and this will be some of the strongest evidence yet to support the benefits of cold exposure.

--Dean

---------

[1] Endocrinology. 2016 Dec;157(12):4744-4753. Epub 2016 Oct 14.

Brown Adipose Tissue Function Is Enhanced in Long-Lived, Male Ames Dwarf Mice.

Darcy J(1), McFadden S(1), Fang Y(1), Huber JA(1), Zhang C(1), Sun LY(1), Bartke 
A(1).

Ames dwarf mice (Prop1df/df) are long-lived due to a loss of function mutation,

resulting in deficiency of GH, TSH, and prolactin. Along with a marked extension 
of longevity, Ames dwarf mice have improved energy metabolism as measured by an
increase in their oxygen consumption and heat production, as well as a decrease
in their respiratory quotient. Along with alterations in energy metabolism, Ames 
dwarf mice have a lower core body temperature. Moreover, Ames dwarf mice have
functionally altered epididymal white adipose tissue (WAT) that improves, rather 
than impairs, their insulin sensitivity due to a shift from pro- to
anti-inflammatory cytokine secretion. Given the unique phenotype of Ames dwarf
epididymal WAT, their improved energy metabolism, and lower core body
temperature, we hypothesized that Ames dwarf brown adipose tissue (BAT) may
function differently from that of their normal littermates. Here we use histology
and RT-PCR to demonstrate that Ames dwarf mice have enhanced BAT function. We
also use interscapular BAT removal to demonstrate that BAT is necessary for Ames 
dwarf energy metabolism and thermogenesis, whereas it is less important for their
normal littermates. Furthermore, we show that Ames dwarf mice are able to
compensate for loss of interscapular BAT by using their WAT depots as an energy
source. These findings demonstrate enhanced BAT function in animals with GH and
thyroid hormone deficiencies, chronic reduction of body temperature, and
remarkably extended longevity.

DOI: 10.1210/en.2016-1593 
PMCID: PMC5133358
PMID: 27740871  [Indexed for MEDLINE]

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

[2] Aging (Albany NY). 2018 Oct 18;10(10):2709-2722. doi: 10.18632/aging.101582.

Increased environmental temperature normalizes energy metabolism outputs between 
normal and Ames dwarf mice.

Darcy J(1)(2)(3), McFadden S(1), Fang Y(1), Berryman DE(4)(5)(6), List EO(4),
Milcik N(1), Bartke A(1).

Ames dwarf (Prop1df) mice possess a loss-of-function mutation that results in

deficiency of growth hormone, prolactin, and thyroid-stimulating hormone, as well
as exceptional longevity. Work in other laboratories suggests that increased
respiration and lipid utilization are important for maximizing mammalian
longevity. Interestingly, these phenotypes are observed in Ames dwarf mice. We
recently demonstrated that Ames dwarf mice have hyperactive brown adipose tissue 
(BAT), and hypothesized that this may in part be due to their increased surface
to mass ratio leading to increased heat loss and an increased demand for
thermogenesis. Here, we used increased environmental temperature (eT) to
interrogate this hypothesis. We found that increased [environmental temperature] diminished BAT activity
in Ames dwarf mice, and led to the normalization of both VO2 and respiratory
quotient between dwarf and normal mice, as well as partial normalization (i.e.
impairment) of glucose homeostasis in Ames dwarf mice housed at an increased eT. 
Together, these data suggest that an increased demand for thermogenesis is
partially responsible for the improved energy metabolism and glucose homeostasis 
which are observed in Ames dwarf mice
.

DOI: 10.18632/aging.101582 
PMCID: PMC6224234
PMID: 30334813 

 

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

[3] Front Genet. 2012 Dec 13;3:288. doi: 10.3389/fgene.2012.00288. eCollection 2012.

Metabolic characteristics of long-lived mice.

Bartke A(1), Westbrook R.

Author information: 
(1)Division of Geriatrics Research, Department of Internal Medicine, Southern
Illinois University School of Medicine Springfield, IL, USA.

Genetic suppression of insulin/insulin-like growth factor signaling (IIS) can
extend longevity in worms, insects, and mammals. In laboratory mice, mutations
with the greatest, most consistent, and best documented positive impact on
lifespan are those that disrupt growth hormone (GH) release or actions. These
mutations lead to major alterations in IIS but also have a variety of effects
that are not directly related to the actions of insulin or insulin-like growth
factor I. Long-lived GH-resistant GHR-KO mice with targeted disruption of the GH 
receptor gene, as well as Ames dwarf (Prop1(df)) and Snell dwarf (Pit1(dw)) mice 
lacking GH (along with prolactin and TSH), are diminutive in size and have major 
alterations in body composition and metabolic parameters including increased
subcutaneous adiposity, increased relative brain weight, small liver,
hypoinsulinemia, mild hypoglycemia, increased adiponectin levels and insulin
sensitivity, and reduced serum lipids. Body temperature is reduced in Ames,
Snell, and female GHR-KO mice. Indirect calorimetry revealed that both Ames dwarf
and GHR-KO mice utilize more oxygen per gram (g) of body weight than sex- and
age-matched normal animals from the same strain. They also have reduced
respiratory quotient, implying greater reliance on fats, as opposed to
carbohydrates, as an energy source. Differences in oxygen consumption (VO(2))
were seen in animals fed or fasted during the measurements as well as in animals 
that had been exposed to 30% calorie restriction or every-other-day feeding.
However, at the thermoneutral temperature of 30°C, VO(2) did not differ between
GHR-KO and normal mice. Thus, the increased metabolic rate of the GHR-KO mice, at
a standard animal room temperature of 23°C, is apparently related to increased
energy demands for thermoregulation in these diminutive animals. We suspect that 
increased oxidative metabolism combined with enhanced fatty acid oxidation
contribute to the extended longevity of GHR-KO mice.

DOI: 10.3389/fgene.2012.00288 
PMCID: PMC3521393
PMID: 23248643 
 

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12 hours ago, Dean Pomerleau said:

Sigh... Except that I've shown you here that living in a colder climate does correlated positively with longer lifespan in a study of nearly 100 different species whose habitats range over many different latitudes.

And I've explained to you repeatedly why you shouldn't expect to see it in humans for a variety of reasons (see here).

Actually, what you've posted is hardly compelling evidence for anything. Repeating it doesn't change that.

I have posted studies showing that cold weather results in spikes in mortality -- the fact is that more people die during the winter months than during the summer. Virtually all Blue Zones are in temperate or warm climate and Southern Europe enjoys greater longevity than Northern Europe, despite significant disparities in income and access to advanced healthcare in the North's favor.

Again, you seem content to accept population studies to support your beliefs in other areas, but ignore them or attack them here.

 

12 hours ago, Dean Pomerleau said:

OMG. I can't believe you actually said that. First of all, your wrong and you clearly didn't even bother to check. ...

There are no marked longevity differences between native populations at warm or cold latitudes and there is no study I have seen which claims that there are. Again, if anything, warm and temperate climate zones appear to be more conducive to longevity when looking at entire populations.

I used "Bushmen" and "Inuits" to illustrate a point. But your response, citing Inuit life expectancy (not necessarily related to longevity) is facetious, or at best, irrelevant: Canada provides considerably better healthcare access and financial support nowadays than found in Angola. Here is a much more accurate estimate of Inuit life expectancy, in 1965:

"[L]ife expectancy of the Eskimo is about 32 years. …" 
http://perfecthealthdiet.com/2011/07/serum-cholesterol-among-the-eskimos-and-inuit/

And here is something comparing the Inuit to the Masai in terms of diet, but from which it would appear that the Masai are in fact healthier overall: https://nutritionstudies.org/masai-and-inuit-high-protein-diets-a-closer-look/

 

12 hours ago, Dean Pomerleau said:

You've alluded to "short term" benefits of CE before. I challenged you there and I challenge you again to provide actual evidence to back of the idea of diminishing benefits of CE over time (e.g. on glucose metabolic). So far you have just expressing your (misguided) opinion, as far as I can tell.

Perhaps if you can look beyond BAT in short term experiments, you can see why things are not quite as simple as freezing oneself and finding longevity.

First, again, if your theory was right over long periods of time, population studies would show a longevity trend expressed at higher latitudes (for some other species, there is such evidence). But population studies do not show such evidence and in fact the opposite is more likely.

Second, while BAT increases may be beneficial, longer term cold exposure has its drawbacks and it may be accompanied by WAT increases which provide insulation effect. This is also noted in the study I posted above, together with the finding that cold air and cold water exposure may produce opposite metabolic effects.

See also this, which supports the study I posted above:

"Due to its high energy consuming characteristics, brown adipose tissue (BAT) has been suggested as a key player in energy metabolism. Cold exposure is a physiological activator of BAT. Intermittent cold exposure (ICE), unlike persistent exposure, is clinically feasible. The main objective of this study was to investigate whether ICE reduces adiposity in C57BL/6 mice. Surprisingly, we found that ICE actually increased adiposity despite enhancing Ucp1 expression in BAT and inducing beige adipocytes in subcutaneous white adipose tissue. ICE did not alter basal systemic insulin sensitivity, but it increased liver triglyceride content and secretion rate as well as blood triglyceride levels. Gene profiling further demonstrated that ICE, despite suppressing lipogenic gene expression in white adipose tissue and liver during cold exposure, enhanced lipogenesis between the exposure periods. Together, our results indicate that despite enhancing BAT recruitment, ICE in mice increases fat accumulation by stimulating de novo lipogenesis.

... our dietary intervention study showed that food restriction did not prevent ICE from causing expansion of adiposity, arguing against hyperphagia as the major cause of ICE-induced fat accumulation. ... Besides mild hyperphagia and de novo adipogenesis of beige cells and white adipocytes in subcutaneous fat, we also found a reduction of lean mass during cold exposure that recovered less robustly than fat mass during non-exposure periods (data not shown). Therefore, we hypothesize that ICE shifts the metabolism in favor of lipogenesis at the expense of muscle anabolism during non-exposure periods, which contributes to the fat accumulation. Although our study did not see any difference in energy expenditure, ICE treatment increased RER during light cycle and diminished the RER oscillation (Fig. 2J&K). This result indicates that ICE alters fuel source of metabolism and further supports the in favoring lipogenesis notion."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4008632/


Third, cold exposure raises blood pressure and cholesterol serum, as well as triglycerides, which for many is a recipe for disaster. A quick search finds stuff like this:

"[The] distribution of ischaemic heart disease (IHD) could be partly explained by variations in degrees of cold exposure, which includes wind and rain as well as temperature, with frequent exposure to cold being more harmful than steady exposure. Blood pressure (BP) and serum cholesterol are raised in response to acute and chronic exposure to cold. ... There are many acute responses to cold which could trigger a myocardial infarction (MI) and therefore cold is probably a major precipitating factor in many cases of MI." https://www.sciencedirect.com/science/article/abs/pii/S0033350605801106

 

I am out of time, but I hope this helps clarify why I don't find compelling your argument that prolonged cold exposure promotes longevity. If you want BAT, there are likely better ways to increase it than freezing. It may be healthier to just eat mushrooms, as Gordo noted above.

At the very least, since it's a well-established fact that cold exposure narrows the arteries, nobody with high blood pressure should be jumping under cold showers.

Cheers.

Edited by Ron Put

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Exercise in Cold Attenuates Increase in BAT Relative to Sedentary Cold Exposure

A couple days ago, Mechanism asked about the combination of cold exposure and exercise, and in particular whether the heat production resulting from exercise might counteract the BAT-boosting benefits of cold exposure.

I just came across this study [1] that pretty strongly suggests that (at least in rodents), exercising in the cold does indeed blunt, and in fact eliminates, the increase in BAT that results from sedentary cold exposure.

The researchers divided rates into four groups for a month: sedentary warm, exercise warm, sedentary cold, exercise cold.

The exercise and cold exposure duration were both two hours, and were simultaneous in the "exercise cold" rats.

Here are screencaptures of an important table and explanatory paragraphs :

zarnrUM.jpg

As you can see, at "warm" temperature (24C which is actually slightly cold for rats), exercise reduced BAT mass relative to sedentary warm controls (222 vs. 294 mg).

More interestingly, the table show that exercising in cold conditions (column 4) boosted BAT relative to exercise in warm conditions (column 2), but much less than BAT was boosted by sedentary cold exposure (column 3) (299 vs. 222 vs 456 mg).

Here is the concluding paragraph of [1]:

immdToq.jpg

In short, cold exercise boosts BAT more than exercise at warm temperature. But if you really want to boost BAT maximally, cold exposure while sedentary is much more effective.

As a result of this, I'm going to continue with my practice of exercising in the cold (when practical). Since I'm going to exercise anyway, this study suggests exercising in cold prevents the loss of BAT that occurs during warm exercise.

But given the BAT-boosting advantage of sedentary cold exposure, I'm also going to continue engaging in cold exposure when relatively sedentary, e.g. cold sleeping conditions, cold shower, and/or wearing my cold vest while hanging out.

--Dean

---------

[1] J Physiol. 1987 Sep;390:45-54.

Exercise during intermittent cold exposure prevents acclimation to cold rats.

Arnold J(1), Richard D.

Author information: 
(1)Department of Physiology, Fac Medicine, Université Laval, Québec, Canada.

1. Energy balance and brown adipose tissue growth were examined in four groups of
male Wistar rats: (i) sedentary, living at 24 degrees C (warm), (ii)
exercise-trained, 2 h daily, living at 24 degrees C, (iii) living at 24 degrees C
but exposed to -5 degrees C, 2 h daily and (iv) living at 24 degrees C but
exercise-trained while being exposed to -5 degrees C, 2 h daily. 2. Cold exposure
during exercise training appeared to have little additional influence on body
composition following 28 days of treatment; body mass gain, in addition to
protein and fat gains, of exercised cold-exposed rats were similar to the gains
observed in exercised warm-exposed control animals. However, in sedentary
cold-exposed rats protein, fat and body mass gains were significantly lower than 
the gains measured in sedentary rats not exposed to cold. 3. Metabolizable energy
intake, expressed mass-independently, was similar in sedentary warm-exposed rats 
and both groups of animals that were exercise-trained. Metabolizable energy
intake was increased almost 15% in sedentary cold-exposed rats. 4. Energy
expenditure (mass independent), excluding the net cost of exercise training, was 
not different in sedentary warm-exposed and exercised rats; energy expenditure
was almost 20% higher in sedentary cold-exposed rats. 5. Total protein and
deoxyribonucleic acid (DNA) contents of brown adipose tissue were more than
doubled in sedentary rats exposed to cold; protein and DNA levels were similar
among the other three groups of rats. 6. Treadmill running during daily, 2 h
exposure at -5 degrees C appears to prevent the cold acclimation responses that
occur in sedentary rats receiving similar cold exposure.

DOI: 10.1113/jphysiol.1987.sp016685 
PMCID: PMC1192165
PMID: 3443942  [Indexed for MEDLINE]
 

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Dean,

Perhaps Rocky was way ahead of his time!!! 

Training in the cold was part of Rocky's strategy in defeating Drago:

rocky+up+snow.jpgrocky-iv-07_510.jpg

 

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Ron,

Thanks for engaging on this. You made three main assertions in your most recent post to this thread. I'll address each of them in turn.

1. Population Studies

You seem to put significant stock in population studies, and in particular the apparent lack of population level evidence in favor of cold exposure based on the climate where different populations live. I'm skeptical of population studies in general due to too many potential confounders except in rare circumstances where the two populations being compared are pretty homogeneous (e.g. vegan vs. omnivorous 7th Day Adventists). I've also tried to explain why expecting population differences in longevity due to climate is unrealistic, due to the prevelance of AC/heating, along with other standard confounders like differences in access to healthcare, dietary habits, exposure to infectious diseases, exercise rates, etc. Plus my hypothesis is that you'll only see significant longevity benefits  from the combination of cold exposure and calorie restriction, which will be very rare in any population. You dismiss these arguments.

Let's agree to disagree.

2. Adverse Cardiovascular Side-effects of Cold Exposure

Here I think we can generally agree. Among the general population, cold conditions can exacerbate cardiovascular issues for people at risk, including risk of heart attack and elevated blood pressure.

But there is evidence [1] that cold adaptation mitigates these risk:

"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 I'll once again agree with you that abrupt exposure to cold is ill-advised for people at elevated risk of adverse cardiovascular events. Fortunately that doesn't include most of us here.

3. Cold Exposure May Elevate WAT, Not Just BAT

The study you referenced on this one [2] was pretty unusual. It exposed mice to cold and compared their body composition, fat metabolism in live mice using an MRI machine, along with measuring insulin sensitivity relative to normally housed mice. It found the usual increase in BAT as a result of CE, but also an increase in the size of several WAT deposits, an increase in weight and no increased insulin sensitivity. One of the WAT deposits showed signs of browning, but the other did not. The authors recognized that the WAT increase, the weight increase and the lack of improvement on glucose metabolism was at odds with most other studies of cold exposure, and were pretty much at a loss to explain it:

This finding of a net increase in fat mass in our ICE mice is in line with a previous mouse study [19], but is at variance with several ICE rodent studies [17], [18], [20]–[22] and the two recent human studies, which either detected a reduction of body fat after 6 weeks of daily 2 h cold exposure [23] or observed no change in adiposity after 10 days of a similar ICE protocol (personal communication with Dr. Wouter D. Van Marken Lichtenbelt) [24]. The discordance is likely multifactorial and may include differences in species and experimental protocols. However, unlike these studies that measured body weight or single fat pad mass at the end of study, we used the highly accurate MRI approach to track body composition throughout the course of ICE treatment. We revealed dynamic changes of body fat during and after cold exposure.

The "dynamic changes of body fat during and after cold exposure" they refer to was interesting. They found that during the quite harsh cold exposure episodes each day (39F/5C for 5h), the mice would burn mostly fat for the first couple hours and eventually have to dip into their lean muscle mass, as measured by their MRI body composition measurement device. Then during the rest of the day (when housed at normal room temperture), they would build back up their white fat and muscle mass. Over the several weeks of the protocol, the net change in lean mass of the cold exposed mice wasn't significant, but for some reason the cold exposed mice synthesized more WAT then they burned off, resulting in a net increase in WAT and body weight. Perhaps it was to increase their insulation against the very cold conditions, as I think you may have speculated.

While interesting, this study seems to be a real outlier when it comes to the effects of CE on body weight, WAT mass and (lack of) glucose metabolism improvements. I personally I don't see any sign of increased fat mass as a result of CE - quite the opposite in fact, at least as measured by my body fat scale (admittedly not the most accurate measure). And my glucose metabolism appears to be improved as well. 

Plus, I would never recommend anyone engage in the extreme level of CE these mice were exposed to (39F/5C for 5h per day).

--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.

Full text: https://academic.oup.com/qjmed/article/92/12/747/1536651

Comment in
    QJM. 2000 Jun;93(6):385-7.
    QJM. 2000 Mar;93(3):197-8.

DOI: 10.1093/qjmed/92.12.747 
PMID: 10581338  [Indexed for MEDLINE]
 

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

[2]  PLoS One. 2014 May 2;9(5):e96432. doi: 10.1371/journal.pone.0096432. eCollection 

2014.

Intermittent cold exposure enhances fat accumulation in mice.

Yoo HS(1), Qiao L(1), Bosco C(1), Leong LH(1), Lytle N(1), Feng GS(2), Chi NW(3),
Shao J(1).

Due to its high energy consuming characteristics, brown adipose tissue (BAT) has 

been suggested as a key player in energy metabolism. Cold exposure is a
physiological activator of BAT. Intermittent cold exposure (ICE), unlike
persistent exposure, is clinically feasible. The main objective of this study was
to investigate whether ICE reduces adiposity in C57BL/6 mice. Surprisingly, we
found that ICE actually increased adiposity despite enhancing Ucp1 expression in 
BAT and inducing beige adipocytes in subcutaneous white adipose tissue. ICE did
not alter basal systemic insulin sensitivity, but it increased liver triglyceride
content and secretion rate as well as blood triglyceride levels. Gene profiling
further demonstrated that ICE, despite suppressing lipogenic gene expression in
white adipose tissue and liver during cold exposure, enhanced lipogenesis between
the exposure periods. Together, our results indicate that despite enhancing BAT
recruitment, ICE in mice increases fat accumulation by stimulating de novo
lipogenesis.

DOI: 10.1371/journal.pone.0096432 
PMCID: PMC4008632
PMID: 24789228  [Indexed for MEDLINE]
 

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Any intervention, including any drugs of course require a clearly delineated protocol. I guess that’s my hobbyhorse. Protocol. Those who’ve paid attention, know from my posts here that it’s what I focus on immediately whenever a new intervention/drug is introduced - “what is the optimal protocol?”. At least partially that’s due to the wisdom of millennia - “the dose makes the poison”. 

Wrt. the mice study, Ron and Dean, doesn’t it stand to reason that when you expose mice to a CE intervention, you need to pay close attention to protocol? Perhaps at one level of temperature and time exposure you’d get beneficial effects, while at a different one, it might be detrimental. So to me, it is never enough to say - “do X”. I always want to ask “X how?”

And perhaps it’s the same with these mice - the “dose makes the poison” and so both claims for and against can be true, and the only way to resolve it is through narrowing or more precisely defining the parameters, with the outer limits being the extremes of “only harm” and “only benefits” - it’s somewhere along that axis, not at the extremes.

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3 hours ago, Dean Pomerleau said:

Plus, I would never recommend anyone engage in the extreme level of CE these mice were exposed to (39F/5C for 5h per day).

Wim Hof does not agree.

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Nice find Dean on CE during exercise vs sedentary activity.  If the effort of sustaining CE during exercise exceeds the marginal benefit of holding on to a small amount of BAT ( ie the difference vs not using CE  during exercise which needs to be quantified to assess for significance ), this trade off may not be worthwhile for everyone here; it does however suggest where to place the most effort for someone committed to focusing on one CE practice to promote beige adipose tissue.

 

Part 1 - On Tom’s point, re: individual variation ( ie, intraspecies) & inter-species variation in dose-response

Study of a very different organism ( rotifers) and mechanism ( not BAT / beige adipose tissue), but underscores even in far simpler model organisms how much variance can be seen by species via disparate regulatory pathway variations https://www.sciencedirect.com/science/article/pii/S0531556518305011?via%3Dihub ( Source: Congeneric variability in lifespan extension and onset of senescence suggest active regulation of aging in response to low temperature ).

Trend is favorable, but vastly different in magnitude, and with exceptions.

I have no doubt at this point that BAT, like exercise and limiting calories can be beneficial, particular in the setting of metabolic pathology such as obesity, hyperinsulinemia and Insulin resistance.  Additionally CE theory has a lot going for it including at a fundamental mechanism level, but the magnitude of the effect in healthy humans for the prevention of disease states is far from certain: Put another way, in seeking external validity of this model to our personal situation, we should keep in mind that CR society members - even those who do not practice formal CR - are likely more akin to the slightly calorically restricted control primates in the NIA-CR study.

Is it necessary - and if so how much of a dose - for a certain degree of optimized health ( I am talking healthspan, not lifespan here) in an already otherwise optimized individual remains an open question, hence the lively debate.

Even in cases of with less ambiguity as to benefit,  for a given intervention it’s risk/benefit profile no doubt varies by species, individual within that species, other health practices, and as detailed in the more recent post by Tom the intervention dose/protocol as well.  Particularly with interventions with potential for greater harm, having some level of confidence ( ie, probability)  that the dose in a given person is in the beneficial or neutral range at worse is especially prudent.  At a minimum, what level of exposure to CE is intermittent vs continuous , etc.

Part 2- ( on the role of population science evidence in the absence of definitive interventional studies for hard measures in people):

Population data has all sorts of issues related to interpretation and potential confounding, but given the limits on definitive RCT evidence in man and other sources of data it is nevertheless one “pillar of longevity” worth considering as part of the overall appraisal of evidence from all sources.  

On the epidemiology side I understand the argument regarding a low signal to noise given the enormity of human variation in lifestyle practices relative to other species, and I agree with your cogent argument that any CE exposure-response relationship can be missed ( type II error) or statistically confounded in casual ecologic observations comparing different populations.  

Perhaps one reason similar arguments continue to be presented here is because of the principal that the exception breaks the rule — For example while not all the Blue Zones are super skinny, even the seventh day Adventists while far outweighing the skinny traditional Okinawans ( BMI for al its thorns) nevertheless are still slim in a relative sense compared to Americans and are within the range of reasonable healthy weights.  Likewise, all blue zones tend to have whole foods.   It seems to me for longevity and healthspan to achieve some of the highest levels - provided no unusual genetic variation - there can be no one major barrier to optimal healthspan.   Genetics can accomplish this too in isolated societies and it has been observed that the Blue Zones are comparatively isolated and additionally indeed some genetic factors have been identified for example in Sardinia and even Okinawa to a degree, but with the possible exception of Sardinia so far the genetic factors have not seemed to outweigh environmental and indeed migration studies and changing lifestyle practices associated with loss of longevity ( esp in Okinawa) suggest a predominantly environmental influence.

In either case, that a wide variety of societies achieving relative longevity and health at a population level with no reason to assume greater CE but quite the opposite suggests CE is not an absolute requirement for commiserate longevity and healthspan while leaving open the possibility that CE may certainly enhance it depending on the individual and context.   These arguments focus on Blue Zone type health, not life extension beyond this which I believe we both share skepticism regarding.

The data with rodents is much more compelling on CE and for such organisms and it may very well be that based on the research you compiled thermonuclear conditions either prevent or attenuate CR, or require a greater extent of dietary restriction or net calorie deficit to achieve CR like outcomes.  Even there we need more study including relocation studies to confidentially ascribe differences in outcomes to CE.  

Now we can appreciate the argument, hey since this is uncertain and animal models are the basis of extrapolation to people, if you are practicing CR, should’t You practice CE too for added insurance?  

Well, sure maybe if it is harmless but it is not so simple.  Some practitioners would demand a higher level of evidence, which is a subjective value-based assessment where to draw the line on the possibility of it being conditional; the data is not inconvertible, but more is a hypothesis ( there is better data on CR effects independent of TRF feeding windows , AGE byproducts, etc. and even this is not utterly without controversy).  

While the benefits of adding CE to an optimized lifestyle in human is less well characterized, you need to get pretty skinny before you see any apparent ill effects rather than incremental additional healthspan via some measure of CRON.  For that reason choosing at least mild CR along with other well validated healthspan enhancing practices not for longevity per se, but for a more Blue Zone like healthspan, may represent lower hanging fruit.  

Since you are already optimized AFAIK and you enjoy CE, I can understand why you don’t mind adding it on as an extra hedge.  Especially since your focus is on conjecture that “you'll only see significant longevity benefits  from the combination of cold exposure and calorie restriction

For others, if they are seeking  Blue Zone like health rather than some hypothetical ( and for people likely to be modest in magnitude of present, particularly since the longer lived Okinawans already were on some degree of CR so this may be about as good as it gets ) step function like increase in lifespan above and beyond that, and are additionally slim, active, and metabolically healthy, etc., they may remain skeptical and may not be unreasonable to determine that the best evidence available at least as of today, does not suggest that formal rigorous CE is an absolute requirement to attain such lifelong good health.

Edits 7/4/19 3:pm incorporating elements of most recent post

Edited by Mechanism

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12 hours ago, Todd Allen said:

Wim Hof does not agree.

So what?

As I've said before, having listened to several of Wim's talks, I was disappointed. He is impressive for his feats of human endurance and mental toughness, but didn't come across as very knowledgeable about CE science or even very articulate about its benefits.

He reminds me of David Blane. In fact both have  done ice challenges. But neither of them strike me as the kind of person I'd go to for medical advice. 

--Dean

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1 hour ago, Dean Pomerleau said:

He is impressive for his feats of human endurance and mental toughness, but didn't come across as very knowledgeable about CE science or even very articulate about its benefits.

39F for 5 hours per day sounds like extreme CE.  But most of us haven't pushed our limits of cold adaptation and we don't have a lot of data to know how far people can or should go with it.  Wim's feats are an example of what is possible and it is well beyond 39F for 5 hours.  I don't think we have clear cut answers to where things such as exercise and caloric restriction transition from beneficial to detrimental and we have less data for CE.

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Humans with Mutation that Boosts UCP1-UCP4 Live Longer

Before I get into the meat of this post, I want to express agreement with Tom and Mechanism. Tom - you're right that "the dose makes the poison" for any intervention, and CE is no different. It is possible to go too far, or not far enough and those boundaries almost certainly vary by individual.

Mechanism, I agree that there are a lot of lower hanging fruit for health / longevity than CE - e.g. a healthy diet, maintaining a healthy weight, exercise, not smoking etc. But if you've already done all those and are still looking for an edge, and particularly if you are practicing CR in hopes of lifespan benefits, CE seems like the next logical step based on (admittedly indirect) evidence from rodents and surrogate markers (e.g. improved insulin sensitivity, reduced inflammation, improved immune response etc) in humans.

Speaking of indirect evidence in humans favoring the longevity effects of CE, consider the following.

As I've argued with Ron, it's usually really hard to draw conclusions from population studies due to the inevitable effects of confounders. The two populations being compared almost invariably differ in many more ways than the one factor you are trying to study (e.g. exposure to cold).

But one pretty effective way to get around this problem is using a method called mendelian randomization. The basic idea is to identify two populations that naturally differ from each other along a dimension you care about due to genetic variation. With a big enough sample of people with and without the mutation, you can assume that other potential confounders that might otherwise muddy the waters even out in the wash.

One area where mendelian randomization studies have been used is to show lifelong elevated LDL cholesterol is associated with an increased risk of cardiovascular disease. The authors of [1] looked at 80K people who'd suffered a heart attack or stroke to see if they had genetic variations that naturally tends to result in elevated LDL and whose only effect is thought to be elevated LDL.

Sure enough, for every 1mmol/L (40 mg/dL) increase in LDL as a result of genetic variation, there was a 50% increase in risk of CHD. The nice thing is that with such a large population size and with the arbitrary nature of who gets (and who doesn't get) the "bad" gene mutations, you can (relatively) safely ignore the effects of other factors that might influence risk of heart disease (e.g. poor diet), since they should even out between the two otherwise comparable populations. As a result, mendelian randomization studies like [1] make for fairly compelling evidence regarding causality from population data.

With that as background, we come to two studies [2][3] that used a technique similar to mendelian randomization to investigate the association between variations in the genes for "uncoupling proteins" (UCPs) and longevity in humans.

Uncoupling proteins allow hydrogen ions (i.e. protons) to leak across the mitochondria inner membrane, rather than going through the normal pathway to generate ATP. As a result, uncoupling proteins generate heat rather than metabolically useful ATP. Three of the UCPs (UPC1, UCP2 and UCP3) are up-regulated by cold exposure in brown adipose tissue and other tissues to boost thermogenesis. In addition, by leaking protons across the mitochondrial membrane, UPCs reduce the proton gradient (i.e. the difference in proton concentration inside vs. outside the mitochondrial membrane). It is widely thought that this gradient, and particularly the high concentration of free protons just outside the mitochondrial membrane, results in "stealing" electrons from other molecules to generate harmful, pro-aging, "free radical" ions (Reaction Oxygen Subspecies - ROSs). So by reducing this proton gradient, UCPs are thought to reduce ROS production and therefore have the potential to be anti-aging.

It's a nice story, but parts of it are somewhat speculative. In particular, it isn't clear just how detrimental ROSs are for health and longevity. For example, ROSs are also thought to sometimes play an important signaling role in the body.

So that's why studies [2] and [3] are interesting. Analogous to the LDL study [1], the authors of study [2] and [3] (same authors for both) looked at a population of ~900 elderly people from southern Italy to see if having gene variants that naturally boost UCP1, UCP2, UCP3 and/or UCP4 expression is associated with living to a very old age. They are both complicated papers, but the short answer is yes - genetic mutations that elevate expression of these four UCPs are associated with longer lifespan in humans.

In the discussion section of [1], which focused on UCP1 (the UCP most up-regulated by cold and expressed mostly in BAT), the authors observed that having the A-C variant of a gene that promotes UCP1 expression is 20% higher in those that live the longest compared with those who are on average 15 years younger. They say:

"On the whole, these results indicate that the A-C haplotype [of a gene that promotes UCP1 expression] has a recessive and beneficial effect, while the G-A haplotype has a dominant and deleterious effect on human aging and longevity."

They then cite evidence that humans with the longevity-associated A-C variant of this UCP1 promoter gene have a higher metabolic rate (sorry Ron). They then conclude:

The survival advantage exerted by the A-C haplotype could then be a consequence of
protection towards age-related decline of energy expenditure.
These
results seem to be in line with those reported by Rizzo et al. (2005)
showing that very old individuals have a higher metabolic rate than
older individuals
. Human cohort studies also support a relationship
between advanced age and body temperature (Waalen and Buxbaum,
2011), suggesting that the individual's ability to maintain a lower
steady state body temperature may affect longevity.
Although skeletal
muscles may play a role in non shivering thermogenesis (Wijers et al.,
2008), the age-related diminished thermogenic activity of BAT might
be the primary cause for the loss of thermoregulation
(Son'Kin et al.,
2010).

The upshot of [2] appears to be that having a gene variant that boost your metabolism through extra UPC1-mediated thermogenesis is associated with living longer.

Study [3] by the same authors found basically the same relationship with three other uncoupling proteins, UCP2, UCP3 and UCP4 - higher expression of them is associated with increased longevity. UCP1, UCP2 and UCP3 are all expressed in BAT, and the second two in skeletal muscles also. The expression of all three is upregulated by cold exposure.

In short, these studies and related studies of UCPs suggest that people who have naturally higher expression of UCPs due to genetic variation have a higher metabolic rate and live longer.

This human evidence aligns nicely with the evidence I discussed a couple days ago, where long-lived dwarf mice naturally exhibit increased thermogenesis as a result of genetic variations that ultimately upregulate the UCP1 in BAT and increase their metabolic rate.

If you aren't lucky enough to have the gene variants that boost the expression of these UCPs naturally, an alternative way to boost their expression is cold exposure. The speculation is that higher expression of these UCPs is causal in longevity (perhaps through less damage from ROSs and/or better insulin sensitivity), and so alternative non-genetic means of boosting them (e.g. cold exposure) will have the same lifespan extending effects.

--Dean

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

[1] Neurology. 2019 Mar 12;92(11):e1176-e1187. doi: 10.1212/WNL.0000000000007091.
Epub 2019 Feb 20.

Relative effects of LDL-C on ischemic stroke and coronary disease: A Mendelian
randomization study.

Valdes-Marquez E(1), Parish S(1), Clarke R(1), Stari T(1), Worrall BB(1);
METASTROKE Consortium of the ISGC,, Hopewell JC(2).

OBJECTIVE: To examine the causal relevance of lifelong differences in low-density

lipoprotein cholesterol (LDL-C) for ischemic stroke (IS) relative to that for
coronary heart disease (CHD) using a Mendelian randomization approach.
METHODS: We undertook a 2-sample Mendelian randomization, based on summary data, 
to estimate the causal relevance of LDL-C for risk of IS and CHD. Information
from 62 independent genetic variants with genome-wide significant effects on
LDL-C levels was used to estimate the causal effects of LDL-C for IS and IS
subtypes (based on 12,389 IS cases from METASTROKE) and for CHD (based on 60,801 
cases from CARDIoGRAMplusC4D). We then assessed the effects of LDL-C on IS and
CHD for heterogeneity.
RESULTS: A 1 mmol/L higher genetically determined LDL-C was associated with a 50%
higher risk of CHD (odds ratio [OR] 1.49, 95% confidence interval [CI] 1.32-1.68,
p = 1.1 × 10-8).
By contrast, the causal effect of LDL-C was much weaker for IS
(OR 1.12, 95% CI 0.96-1.30, p = 0.14; p for heterogeneity = 2.6 × 10-3) and, in
particular, for cardioembolic stroke (OR 1.06, 95% CI 0.84-1.33, p = 0.64; p for 
heterogeneity = 8.6 × 10-3) when compared with that for CHD.
CONCLUSIONS: In contrast with the consistent effects of LDL-C-lowering therapies 
on IS and CHD, genetic variants that confer lifelong LDL-C differences show a
weaker effect on IS than on CHD. The relevance of etiologically distinct IS
subtypes may contribute to the differences observed.

Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on
behalf of the American Academy of Neurology.

DOI: 10.1212/WNL.0000000000007091 
PMCID: PMC6511103
PMID: 30787162 
 

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

[2] Exp Gerontol. 2011 Nov;46(11):897-904. doi: 10.1016/j.exger.2011.07.011. Epub

2011 Jul 30.

Two variants located in the upstream enhancer region of human UCP1 gene affect
gene expression and are correlated with human longevity.

Rose G(1), Crocco P, D'Aquila P, Montesanto A, Bellizzi D, Passarino G.

Author information: 
(1)Department of Cell Biology, University of Calabria, Rende, Italy.
pinarose@unical.it

The brown fat specific UnCoupling Protein 1 (UCP1) is involved in thermogenesis, 
a process by which energy is dissipated as heat in response to cold stress and
excess of caloric intake. Thermogenesis has potential implications for body mass 
control and cellular fat metabolism. In fact, in humans, the variability of the
UCP1 gene is associated with obesity, fat gain and metabolism. Since regulation
of metabolism is one of the key-pathways in lifespan extension, we tested the
possible effects of UCP1 variability on survival. Two polymorphisms (A-3826G and 
C-3740A), falling in the upstream promoter region of UCP1, were analyzed in a
sample of 910 subjects from southern Italy (475 women and 435 men; age range
40-109). By analyzing haplotype specific survival functions we found that the A-C
haplotype favors survival in the elderly. Consistently, transfection experiments 
showed that the luciferase activity of the construct containing the A-C haplotype
was significantly higher than that containing the G-A haplotype. Interestingly,
the different UCP1 haplotypes responded differently to hormonal stimuli. The
results we present suggest a correlation between the activity of UCP1 and human
survival, indicating once again the intricacy of mechanisms involved in energy
production, storage and consumption as the key to understanding human aging and
longevity.

Copyright © 2011 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.exger.2011.07.011 
PMID: 21827845  [Indexed for MEDLINE]

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

[3] PLoS One. 2011;6(12):e29650. doi: 10.1371/journal.pone.0029650. Epub 2011 Dec 27.

Further support to the uncoupling-to-survive theory: the genetic variation of
human UCP genes is associated with longevity.

Rose G(1), Crocco P, De Rango F, Montesanto A, Passarino G.

Author information: 
(1)Department of Cell Biology, University of Calabria, Rende, Italy.

In humans Uncoupling Proteins (UCPs) are a group of five mitochondrial inner
membrane transporters with variable tissue expression, which seem to function as 
regulators of energy homeostasis and antioxidants. In particular, these proteins 
uncouple respiration from ATP production, allowing stored energy to be released
as heat. Data from experimental models have previously suggested that UCPs may
play an important role on aging rate and lifespan. We analyzed the genetic
variability of human UCPs in cohorts of subjects ranging between 64 and 105 years
of age (for a total of 598 subjects), to determine whether specific UCP
variability affects human longevity. Indeed, we found that the genetic
variability of UCP2, UCP3 and UCP4 do affect the individual's chances of
surviving up to a very old age. This confirms the importance of energy storage,
energy use and modulation of ROS production in the aging process. In addition,
given the different localization of these UCPs (UCP2 is expressed in various
tissues including brain, heart and adipose tissue, while UCP3 is expressed in
muscles and Brown Adipose Tissue and UCP4 is expressed in neuronal cells), our
results may suggest that the uncoupling process plays an important role in
modulating aging especially in muscular and nervous tissues, which are indeed
very responsive to metabolic alterations and are very important in estimating
health status and survival in the elderly.

© 2011 Rose et al.

DOI: 10.1371/journal.pone.0029650 
PMCID: PMC3246500
PMID: 22216339  [Indexed for MEDLINE]
 

 

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Dean, I saw you just posted this as I updated my post above, in case you are drafting a response off an old copy.  Looking forward to reading your next post above.

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I just read your most recent post.  Comments appreciated, I addressed a few other points there in my edited post above including the Blue Zone data  from another angle WRT the purported necessity ( as opposed to potential helpfulness) of CE.  These comments pertain while at the same time acknowledging the case you made regarding the housing conditions ( vs thermoneutral) from the rodent CR studies.

Besides my other comments in my long post above, keep in mind for Mendelian randomization studies they represent again incremental benefit for the average as opposed to optimized individual, and as you know attempts to push a surrogate variable biomarkers additionally may have unanticipated consequences and the less validated the biomarkers the greater the risk ( take in contrast with LDL, the case of HDL lowering pharmacological interventions with negative or worse outcomes).  Not a perfect example as UCP is better understood and more direct an approach via CE, but the chronic vs intermittent CE study particularly if replicated compels at least some caution attenuated by your monitoring the improvements you have seen in your own ( better validated) biomarkers.  

As also detailed above your motivation for CE varies from mine WRT health goals and practices, so this along with risk/reward appetite in the setting of ambiguity and different interpretations of the portfolio of evidence can lead to reasonable divergent conclusions and the same for Ron Put and others.

i hope some researchers are following this thread in the background as we are sorely in need of better outcomes data following which the heterogeneity and divergence of conclusions may lessen, one way or the other.

Edited by Mechanism

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On that note, I wonder whether Satchin Panda follows this thread.  Within the last 48 hrs he tweeted https://academic.oup.com/edrv/article/38/6/538/4097592 ( hopefully none of us here are burn victims or cancer patients).  I found more on the double edged sword in esp. in special populations here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5234861/

With caveats including the CE exposure doses and obesogenic HFD which does not apply here, at least some of the metabolic sequela ( though not all as we have seen) we discussed may be due to hyperphagia which fortunately is also not a common problem in this “CR” forum ( though noteworthy for a potential decline in BDNF 😕 )  https://www.spandidos-publications.com/mmr/18/4/3923

On a lighter note, while which ones are truly material ( clinically significant at ideas consumed) is another matter, the research community should definitely keep you in mind when they write reviews so that these can address more comprehensive compilations of “Food Ingredients Involved in White-to-Brown Adipose Tissue Conversion and in Calorie Burning” ( your tally puts them to shame ) 😊 https://www.frontiersin.org/articles/10.3389/fphys.2018.01954/full

 

 

Edited by Mechanism

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Mouse Gene That Boosts BAT Extends Lifespan

In two recent posts (here and here) I presented evidence that:

  1. Dwarf mice have hyperactive BAT and live longer, and
  2. People with more active BAT as a result of genetic mutations that upregulate uncoupling proteins live longer.

Here I present another study [1] in mice that found mutation to a gene (Pten) has the following effects:

  • Elevated BAT activity and browning of WAT via higher UCP1 (via this pathway).
  • Increased energy expenditure and food consumption (~60% more per gram BW!)
  • Reduced body weight and adiposity
  • Improved insulin sensitivity and lower fasting glucose
  • Extended mean lifespan (12%) and maximum 10% lifespan (11%)

Here are the survival curves of the BAT-boosted Pten mice (blue) vs. wild-type mice (black) when both were given free access to normal rodent chow for their entire lives: 

           gr2.jpg

Here are the graphs of glucose, insulin and IGF-1, all of which were lower in the Pten mice:

        gr3.jpg

The organ in the lower right of the diagram shows the livers from WT and Pten mice after high-fat feeding for 10 months, showing the WT mice develop "fatty liver" but the Pten mice don't. All the other graphs above (except D and E) are comparisons Pten and WT mice fed normal chow ad-lib.

So once again we see evidence that boosting BAT (via genetics) increases metabolism, improves metabolic health, and extends lifespan.

--Dean

Update: Shortly after I wrote the above I came across study [2] which basically found the exact same thing as [1]. Namely, a genetic manipulation (knockout of the gene RGS14) which boosts BAT in mice increases their metabolic rate, reduced body weight and WAT mass (despite eating more), improved their metabolic health (and appearance!), and most importantly, increased their mean and maximum lifespan by 17% and ~17% respectively. 

Here are the survival graphs, along with a picture of the mangy normal mice (left), sleek BAT-boosted mice (middle) and sleek normal mice who had BAT from the BAT-boosted mice surgically implanted at age 4 months. Each of the three mice pictured is ~750 days old, which was the median survival age of the normal mice.

   acel12751-fig-0001-m.jpg

Here is the amusing thing the researchers said about the appearance of the various groups of mice:

 It is also important that BAT protects against the aging phenotype, for example, graying and loss of hair, dermatitis, and hunched back, all of which were observed in old WT mice, but not observed in old RGS14 KO mice or in old WT mice, which received BAT transplants. 

Surgically removing the BAT from the knockout mice erased their metabolic benefits of their mutation. Conversely, surgically implanting the BAT from the knockout mice into normal mice improved their metabolism. No lifespan data was reported on these surgically manipulated mice.

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

[1] Cell Metab. 2012 Mar 7;15(3):382-94. doi: 10.1016/j.cmet.2012.02.001.

Pten positively regulates brown adipose function, energy expenditure, and
longevity.

Ortega-Molina A(1), Efeyan A, Lopez-Guadamillas E, Muñoz-Martin M, Gómez-López G,
Cañamero M, Mulero F, Pastor J, Martinez S, Romanos E, Mar Gonzalez-Barroso M,
Rial E, Valverde AM, Bischoff JR, Serrano M.

Aging in worms and flies is regulated by the PI3K/Akt/Foxo pathway. Here we

extend this paradigm to mammals. Pten(tg) mice carrying additional genomic copies
of Pten are protected from cancer and present a significant extension of life
span that is independent of their lower cancer incidence. Interestingly, Pten(tg)
mice have an increased energy expenditure and protection from metabolic
pathologies. The brown adipose tissue (BAT) of Pten(tg) mice is hyperactive and
presents high levels of the uncoupling protein Ucp1, which we show is a target of
Foxo1. Importantly, a synthetic PI3K inhibitor also increases energy expenditure 
and hyperactivates the BAT in mice. These effects can be recapitulated in
isolated brown adipocytes and, moreover, implants of Pten(tg) fibroblasts
programmed with Prdm16 and Cebpβ form subcutaneous brown adipose pads more
efficiently than wild-type fibroblasts. These observations uncover a role of Pten
in promoting energy expenditure, thus decreasing nutrient storage and its
associated damage.

Copyright © 2012 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.cmet.2012.02.001 
PMID: 22405073  [Indexed for MEDLINE]
 

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

[2]  Aging Cell. 2018 Aug;17(4):e12751. doi: 10.1111/acel.12751. Epub 2018 Apr 14.

Enhanced longevity and metabolism by brown adipose tissue with disruption of the 
regulator of G protein signaling 14.

Vatner DE(1), Zhang J(1), Oydanich M(1), Guers J(1), Katsyuba E(2), Yan L(1),
Sinclair D(3), Auwerx J(2), Vatner SF(1).

Author information: 
(1)Department of Cell Biology & Molecular Medicine, Rutgers University-New Jersey
Medical School, Newark, NJ, USA.
(2)Laboratory of Integrative and Systems Physiology, Ecole Polytechnique Fédérale
de Lausanne (EPFL), Lausanne, Switzerland.
(3)Department of Genetics, Harvard Medical School, Boston, MA, USA.

Disruption of the regulator for G protein signaling 14 (RGS14) knockout (KO) in
mice extends their lifespan and has multiple beneficial effects related to
healthful aging, that is, protection from obesity, as reflected by reduced white 
adipose tissue, protection against cold exposure, and improved metabolism. The
observed beneficial effects were mediated by improved mitochondrial function. But
most importantly, the main mechanism responsible for the salutary properties of
the RGS14 KO involved an increase in brown adipose tissue (BAT), which was
confirmed by surgical BAT removal and transplantation to wild-type (WT) mice, a
surgical simulation of a molecular knockout. This technique reversed the
phenotype of the RGS14 KO and WT, resulting in loss of the improved metabolism
and protection against cold exposure in RGS14 KO and conferring this protection
to the WT BAT recipients. Another mechanism mediating the salutary features in
the RGS14 KO was increased SIRT3. This mechanism was confirmed in the RGS14 X
SIRT3 double KO, which no longer demonstrated improved metabolism and protection 
against cold exposure. Loss of function of the Caenorhabditis elegans RGS-14
homolog confirmed the evolutionary conservation of this mechanism. Thus,
disruption of RGS14 is a model of healthful aging, as it not only enhances
lifespan, but also protects against obesity and cold exposure and improves
metabolism with a key mechanism of increased BAT, which, when removed, eliminates
the features of healthful aging.

© 2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley
& Sons Ltd.

DOI: 10.1111/acel.12751 
PMCID: PMC6052469
PMID: 29654651 
 

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Mechanism wrote:

2 hours ago, Mechanism said:

At least some of the metabolic sequela ( though not all as we have seen) we discussed may be due to hyperphagia which fortunately is not a common problem in this “CR” forum ( though noteworthy for a potential decline in BDNF 😕 )  https://www.spandidos-publications.com/mmr/18/4/3923

Thanks Mechanism. This is another interesting study [1] which at first glance seems like an outlier. Researchers found cold exposure coupled with a high fat diet (HFD) did not have the usual metabolic benefits in their mice. In fact, the CE mice ate more and got slightly fatter than mice that weren't cold exposed when both were fed a HFD. In fact, even on normal chow the CE mice didn't weigh any less than non-CE mice and didn't exhibit the improvement in glucose metabolism that normally accompanies cold exposure.

Looking at the methodology details, it appears these researchers used an unusual cold-exposure paradigm:

Half of the mice on each diet were left to stand in ice-cold water, which was 0.5 cm in depth, for 1 h per day for 7 weeks. Non-cold exposed mice also stood on the water but at room temperature. 

The natural conclusion the authors draw is that the stress of one hour of intense cold exposure per day was enough to boost the appetite of the CE mice, but not enough to significantly upregulate their BAT metabolism. This is supported by the fact that they found no increases in BAT mass as a result of cold exposure on either the normal chow or the high fat diet.

The authors speculate about how these results relate to humans and cold exposure thusly:

Humans protect themselves from cold using appropriate clothes and living in heated environments. Concerning this self-protective behavior during our daily life, it is unlikely that human beings are exposed to a cold surrounding for a long period, but transmigrate from cold to warm environments in occasions. Frequently, parts of the human body suffer from cold exposure during winter.

In other words, the average person in a cold climate may be more like the briefly cold-exposed mice in their experiment than CE rodents in other experiments, where the cold exposure paradigm is more prolonged and potentially less acutely stressful. I've suggest to Ron that this is one of several reasons we shouldn't necessarily expect to see people who live in cold climates manifest the benefits of cold exposure - they just aren't regularly exposed to cold for very long due to insulated clothing and indoor heating.

To Tom's point about the importance of protocol, they say:

Further studies are required using cold exposure at different intensities and durations in order to reveal the full association between cold exposure and energy/glucose homeostasis. Potential adverse effects should be taken into consideration when manipulating temperature to stimulate the browning of white fat.

Fortunately, we have good data from humans it doesn't take continuous cold exposure to increase BAT and thermogenic capacity. Cold exposure for a couple hours per day does indeed boost BAT activity and thermogenesis in people. On the other hand, this data suggests it is unlikely a brief cold shower will be effective at boosting BAT. Another takeaway would be avoid pigging out on a high fat diet when practicing CE, which is in line with my hypothesis that mild CR plus cold exposure is the best way to go.

--Dean 

---------

[1] Mol Med Rep. 2018 Oct;18(4):3923-3931. doi: 10.3892/mmr.2018.9382. Epub 2018 Aug 

10.

Cold exposure promotes obesity and impairs glucose homeostasis in mice subjected 
to a high‑fat diet.

Zhu P(1), Zhang ZH(1), Huang XF(2), Shi YC(3), Khandekar N(3), Yang HQ(1), Liang 
SY(1), Song ZY(1), Lin S(1).

Cold exposure is considered to be a form of stress and has various adverse

effects on the body. The present study aimed to investigate the effects of
chronic daily cold exposure on food intake, body weight, serum glucose levels and
the central energy balance regulatory pathway in mice fed with a high‑fat diet
(HFD). C57BL/6 mice were divided into two groups, which were fed with a standard 
chow or with a HFD. Half of the mice in each group were exposed to ice‑cold water
for 1 h/day for 7 weeks, while the controls were exposed to room temperature.
Chronic daily cold exposure significantly increased energy intake, body weight
and serum glucose levels in HFD‑fed mice compared with the control group. In
addition, 1 h after the final cold exposure, c‑fos immunoreactivity was
significantly increased in the central amygdala of HFD‑fed mice compared with
HFD‑fed mice without cold exposure, indicating neuronal activation in this brain 
region. Notably, 61% of these c‑fos neurons co‑expressed the neuropeptide Y
(NPY), and the orexigenic peptide levels were significantly increased in the
central amygdala of cold‑exposed mice compared with control mice. Notably, cold
exposure significantly decreased the anorexigenic brain‑derived neurotropic
factor (BDNF) messenger RNA (mRNA) levels in the ventromedial hypothalamic
nucleus and increased growth hormone releasing hormone (GHRH) mRNA in the
paraventricular nucleus. NPY‑ergic neurons in the central amygdala were activated
by chronic cold exposure in mice on HFD via neuronal pathways to decrease BDNF
and increase GHRH mRNA expression, possibly contributing to the development of
obesity and impairment of glucose homeostasis.

DOI: 10.3892/mmr.2018.9382 
PMCID: PMC6131648
PMID: 30106124  [Indexed for MEDLINE]
 

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