661 replies to this topic

[AlPater]

There is a lot of discussion about brown adipose tissue in the below paper and its reference suggests this healthy fat is possibly part of the means by which CR increases longevity.

 

Obesity and related consequences to ageing.

Jura M, Kozak LP.

Age (Dordr). 2016 Feb;38(1):23. doi: 10.1007/s11357-016-9884-3. Epub 2016 Feb 4.

PMID: 26846415

http://sci-hub.io/10...1357-016-9884-3

 

Abstract

 

Obesity has become a major public health problem. Given the current increase in life expectancy, the prevalence of obesity also raises steadily among older age groups. The increase in life expectancy is often accompanied with additional years of susceptibility to chronic ill health associated with obesity in the elderly. Both obesity and ageing are conditions leading to serious health problems and increased risk for disease and death. Ageing is associated with an increase in abdominal obesity, a major contributor to insulin resistance and the metabolic syndrome. Obesity in the elderly is thus a serious concern and comprehension of the key mechanisms of ageing and age-related diseases has become a necessary matter. Here, we aimed to identify similarities underlying mechanisms related to both obesity and ageing. We bring together evidence that age-related changes in body fat distribution and metabolism might be key factors of a vicious cycle that can accelerate the ageing process and onset of age-related diseases.

 

KEYWORDS:

 

Brown adipose tissue; Expandability; Lean mass; Metabolic syndrome

 

 

"Brown adipose tissue

 

There are two main types of adipose tissues, white

adipose tissue (WAT) that contains a single large lipid

droplet storing excess energy and brown adipose tissue

(BAT) that is characterized by multiple lipid droplets

and large numbers of mitochondria that use lipids to

generate heat (Cannon and Nedergaard 2004; Kozak

et al. 2010a). The cold environment stimulates the sympathetic

nervous system which releases norepinephrine

into BAT to activate β-adrenergic receptors (β-AR).

Brown adipose tissue cells contain uncoupling protein

1 (UCP1), localized in the inner mitochondrial membrane

where it dissipates the membrane potential generated

by respiration fuelled by beta-oxidation of fatty

acids to produce heat (Ricquier 2011) (reviewed by

Cannon and Nedergaard 2004 (Cannon and

Nedergaard 2004)). Additionally, brown adipocytes, also

called brite or beige cells, can be induced in WAT

depots upon cold stimulation (Cannon and Nedergaard

2004; Wu et al. 2012).

 

Human BAT is maximally recruited in early

infancy. Although novel findings have led to a

consensus that metabolically active BAT is present

in most children and many adult humans (Virtanen

et al. 2009; Cypess et al. 2009), BAT deposits are

often undetectable in people who live at

thermoneutrality (23 °C) (Seale and Lazar 2009).

Recent studies suggest that adult human BAT presents

the molecular characteristics of rodent beige

cells rather than classical BAT (Wu et al. 2012).

Animal studies showed relatively stable Ucp1

mRNA levels in adult mice (Xue et al. 2005;

Chabowska-Kita et al. 2015); nonetheless, BAT

activity was shown to diminish in ageing (Seale

and Lazar 2009). It has been suggested that ageing

may be associated with impaired thermogenesis as

suggested by greater reduction of BAT activity in

old men compared to young ones (Seale and Lazar

2009; McDonald and Horwitz 1999; Lin et al.

2014). Additionally, age-dependent loss of thermogenic

capacity is associated with a decline in

UCP1 activity but not in UCP1 protein (Valle

et al. 2008). A study on the effect of age on BAT

found active BAT in only 10 % of the subjects

between 50 and 60 years of age (McDonald and

Horwitz 1999; Yoneshiro et al. 2011). There are

increasing numbers of papers with data interpreted

as showing that decreased amounts of brown fat

may contribute to thermal dysregulation and energy

imbalance often observed in older individuals;

however, it is still uncertain whether the methodology

for quantifying the number of brown adipocytes

and their thermogenic activity in individuals

with variable levels of obesity is accurate (Muzik

et al. 2013).

 

It has been demonstrated that during the process of

ageing, there is an ageing-dependent accumulation of

point mutations in mitochondrial DNA of most subjects

analyzed. Cumulative molecular damage leads to mitochondrial

impairment (Detmer and Chan 2007), and its

functional decline is linked to an age-dependent increase

in the pathogenesis of metabolic disorders and neurodegenerative

diseases (Lin et al. 2014; Detmer and Chan

2007). On the other hand, it has been shown that lifelong

dietary caloric restriction, which decelerates ageing, can

attenuate the age-related decline in mitochondrial mass

and uncoupling protein levels in BAT of rats (Valle et al.

2008). Although it has been proposed that changes in

circulating levels of thyroid and sex hormones might

contribute to the age-related decline in BAT activity

(Mattson 2010), the main components underlying the

dysfunction of BAT in ageing are still unknown (Lin

et al. 2014).

 

BAT function is decreased not only during ageing but

also in obese state. Experimental mouse and human

obesity models evidence that additionally to diminished

or defective BAT function (Himms-Hagen and

Desautels 1978; Avram et al. 2005b; Vijgen et al.

2011; Claessens-van Ooijen et al. 2006; van Marken

Lichtenbelt et al. 2009), obese individuals have blunted

cold-induced thermogenesis and were proposed to have

a larger insulative response (Wijers et al. 2010). Additionally,

genetically obese ob/ob mice were shown to be

cold sensitive, perhaps due to the fact that their BAT is

usually thermogenically inactive, atrophied with low

UCP1 levels (Carter et al. 2013), but also from defects

in centrally controlled thermogenesis. Thus, ob/ob mice

fail to maintain proper body temperature when subjected

to cold treatment (Himms-Hagen and Desautels 1978).

Studies on mice revealed that obesity-prone mouse

strains possess less BAT than obesity-resistant mice

(Collins et al. 1997; Guerra et al. 1998). Also, in transgenic

mice with increased BAT activity due to overexpression

of UCP1, there is enhanced energy expenditure

and resistance to DIO (Kopecky et al. 1995). In morbidly

obese human subjects, expression of UCP1 in BAT

was shown to be significantly reduced in comparison to

lean controls (Vijgen et al. 2011). It is speculated that the

absence of adequate amounts of BAT could lead to a

severe overweight condition (Vijgen et al. 2011; van der

Lans et al. 2013). However, mice with an inactive Ucp1

gene do not have increased susceptibility to DIO (Liu

et al. 2003), leading to an alternative interpretation that

overall, metabolic efficiency is reduced in individuals

with lower levels of UCP1-based thermogenesis (Butler

and Kozak 2010). Other studies, with both genetic and

surgically generated models of classical BAT insufficiency

(Myf5-BMPR1A-KO), suggest the existence of

a physiological mechanism to ensure thermoregulation

by compensatory browning in WAT (Schulz et al. 2013).

Schulz et al. (2013) showed that classical BAT is crucial

during acute cold challenges, but compensatory brown

cells induced in WAT in Myf5-BMPR1A-KO mice

(with severe insufficiency of classical BAT) had a critical

role in normal body temperature maintenance, particularly

in long-term cold exposure (Schulz et al. 2013).

The induction of brown adipocytes in the inguinal fat of

mice with a deficiency in UCP1-based thermogenesis

was originally shown by Liu et al. (Liu et al. 2003). The

idea that brown adipocytes, which can be induced in

white fat depots by adrenergic signaling, constitute a

mechanism for reducing or preventing obesity is still not

settled.

 

As mentioned, beige adipocytes can be induced in

WAT depots (Cannon and Nedergaard 2004), and even

mild cold increases heat production (Claessens-van

Ooijen et al. 2006). It has been proposed that BAT has

functional significance in humans and might be targeted

as a source for the development of anti-obesity treatments.

It has been shown that BAT exerts anti-type 2

diabetic effects associated with improvements of dyslipidemia

and insulin secretion (de Souza et al. 1997;

Peirce and Vidal-Puig 2013). Moreover, recent studies

on rodents have showed that caloric restriction postpones

the age-related decline in BAT mitochondrial

function (Valle et al. 2008) and ghrelin ablation in older

individuals prevents age-associated decline in UCP1

gene expression (Lin et al. 2011). Therefore, it may be

possible to prevent the age-related decrease BAT content

and in consequence decelerate age-related fat mass accumulation

and development of diabetes."

 

 

Caloric restriction retards the age-related decline in mitochondrial function of brown adipose tissue.

Valle A, Guevara R, García-Palmer FJ, Roca P, Oliver J.

Rejuvenation Res. 2008 Jun;11(3):597-604. doi: 10.1089/rej.2007.0626.

PMID: 18593277

http://sci-hub.io/10...9/rej.2007.0626

 

 

Abstract

 

Caloric restriction (CR) has been shown to prevent the age-associated loss of mitochondrial function and biogenesis in several tissues such as liver, heart, and skeletal muscle. However, little is known about the effects of CR on a tissue in which the mitochondria have no adenosine triphosphate (ATP)-producing purpose but show a high degree of uncoupling, namely brown adipose tissue (BAT). Hence, the aim of the present study was to analyze the effect of long-term CR on BAT mitochondrial function and biogenesis. BAT mitochondria obtained from 24-month-old male and female rats previously subjected to 40% CR for 12 months were compared with mitochondria from old (24 months) and young (6 months) ad libitum fed rats. Old restricted rats compared to old ad libitum fed ones showed a reduction in BAT size with respect to fat content and adipocyte number. Mitochondrial DNA content in BAT increased with age and even more so in restricted rats, indicating a summative effect of age and CR on mitochondrial proliferation. CR induced resistance to lose total and mitochondrial protein, COX activity, and uncoupling capacity with advancing age, in relation with a lower decrease of mitochondrial transcription factor A (TFAM). In summary, our results demonstrate CR prevents the age-associated decline in mitochondrial function in BAT, probably in relation with a lower impairment of mitochondrial biogenesis.

[Dean Pomerleau]

Al,

 

Thanks for the new review article (PMID: 26846415). It is a pretty good overview of obesity & aging, and as you said has a pretty long section on brown adipose tissue. Nothing particularly new though.

 

But the other one you pointed to, Valle et al (PMID 18593277), which was reference in the review, turns out to be much more interesting than the review itself. It looked at BAT mass and BAT activity in old rats fed either AL or 40% CRed. It is important to note that all the rats were housed  at 71 °F for the entire experiment, a temperature well below thermal neutrality. 

 

What they found was that BAT mass was reduced in old CRed rats relative to AL-fed old rats, even after adjusting for body weight. Here is the table, with the relevant cells highlighted:

 

 

As you can see, the old CRed rats had about 60% less total brown adipose tissue and about 30% less BAT as a percentage of body weight relative to old AL-fed rats. So in contrast with all those other, health-promoting interventions I've listed that increase the amount of BAT, CR appears to decrease the amount of BAT tissue. This is consistent with the results seen in anorexic women (PMID 23393181; discussed here), none of whom exhibited detectable levels of BAT, even after refeeding to raise their BMI to 19.

 

But here is where it gets most interesting. In the old CR rats the number of mitochondria in BAT cells, and the amount of mitochondrial DNA in BAT cells, was dramatically increased relative to the old AL-fed rats. This resulted in much greater expression of the uncoupling protein UCP1 (with promotes clean burning of fat to produce heat rather than to generate useful energy via ATP) in each BAT cell of CR rats relative to the AL rats. Here is a graph of UCP1 protein in the mitochondria of BAT cells of young (Y), old AL-fed (O) and old calorie restricted (OR) rats. 

 

 

As you can see, CR dramatically increased the amount of uncoupling protein-1 in the mitochondria of BAT cells in both male and female rats. So the CRed rats had both more mitochondria in their BAT cells, and each of the mitochondria had more UPC1. So despite having dramatically less BAT, the BAT the CRed rats did have was more metabolically active, preserving the ability of the CRed rats to generate heat via BAT thermogenesis. Here is the researchers commentary on this result from the discussion section:

 

In broad terms, we observed that old restricted animals compared to old ad libitum fed ones have a reduced BAT size, even normalized per body weight, which probably is due to a lower fat content and adipocyte number in the tissue. ... As happens in liver or skeletal muscle, CR was also shown to promote mitochondrial biogenesis in BAT. On the whole, this conservation of BAT thermogenic capacity may confer several advantages, such as a higher ability to respond to cold exposure or to control body weight when food supply is restored, and, therefore, be part of the rejuvenation mechanisms underlying the life-span extension induced by CR.

 

I find this study really interesting. Here's why. BAT thermogenesis is very metabolically expensive. Just a few ounces of BAT in people can burn hundreds of calories per day. If it were neutral (to say nothing of deleterious) with respect to health / longevity, you would expect nature/evolution to say "the hell with it" and eliminate it as part of the "hunkering down" program that kicks in when calories are scarce. After all, it jettisons nearly all of its white adipose tissue, which is much less metabolically expensive to maintain than BAT. But in rats at least, this isn't the case. Instead, some brown fat, and nearly all BAT thermogenic capacity, is maintained even when calories are severely limited. This suggests to both to me and apparently the authors, as indicated in the bold section of the quote above, that BAT thermogenesis may be part of the "rejuvenation mechanisms" underlying the lifespan benefits of CR. 

 

But several caveats are required in trying to generalize these rodent results to humans. First and most obviously, these were rats and not humans. Among the many differences, rodents express BAT much more readily than adult humans do, likely as a result of their higher need for thermogenesis due to their higher surface-to-volume ratio, and due to the fact that they spend much of their lives below their thermally neutral temperature. Plus, all the rats in this experiment were kept at a temperature well below thermal neutrality. If they were kept in warmer, thermally-neutral conditions, they may have jettisoned what little BAT they retained, and hence their thermogenic capacity, as was seen in this study [1]. And as we saw in this study (PMID 25362635; discussed here), BAT-thermogenesis (resulting from cold exposure) may indeed be necessary for the longevity benefits of CR.

 

So while CR may not increase BAT or BAT-thermogenesis per se, so it doesn't belong on the list I've compiled of BAT-inducers, it does seem to preserve BAT thermogenic capacity despite the high metabolic cost, at least when CRed rodents are kept in cold conditions. This last qualifier is particularly important for humans since we have much less BAT than rodents. In particular, if we humans want to prevent our body from eliminating all its BAT during CR, and I don't think it is too much of a stretch given the evidence to say, if we want to benefit from CR at all, some combination of practices to promote BAT is likely to be necessary. You can take you pick from the list I've compiled in this post, but cold exposure is by far the most effective intervention for promoting BAT.

 

--Dean

 

-----------

[1] Am J Physiol. 1987 Feb;252(2 Pt 1):E237-43.

 

Effect of warm or cold exposure on GDP binding and uncoupling protein in rat

brown fat.

 

Trayhurn P, Ashwell M, Jennings G, Richard D, Stirling DM.

 

The effects of acute and chronic exposure to different environmental temperatures

on the total tissue cytochrome oxidase activity, level of mitochondrial GDP

binding, and specific mitochondrial concentration of uncoupling protein have been

investigated in rat brown adipose tissue, a radioimmunoassay being used to

measure uncoupling protein. Acclimation at different temperatures for 3 wk

produced parallel changes in GDP binding, the concentration of uncoupling

protein, and the activity of cytochrome oxidase, each parameter rising with

decreasing temperature between thermoneutrality (29 degrees C) and 4 degrees C.

Acute exposure of warm-acclimated (29 degrees C) rats to the cold (4 degrees C)

led to a rapid increase in GDP binding without any alteration in the amount of

uncoupling protein. The increase in binding was accompanied by an increase in the

rate of acetate-induced swelling of the mitochondria. The concentration of

uncoupling protein in warm-acclimated rats was significantly raised only after 48

h exposure to cold. When cold-acclimated rats were exposed acutely to the warm,

there was a rapid decrease in GDP binding without any alteration in the amount of

uncoupling protein. It is concluded that after alterations in environmental

temperature the concentration of uncoupling protein in brown adipose tissue

mitochondria changes much more slowly than GDP binding and that binding can

therefore be dissociated from the amount of the protein.

 

PMID: 3826341

[Dean Pomerleau]

All,

 

By now we are all quite familiar with the somewhat disappointing results in the CR monkey studies, particularly the failure 30% CR to extend the lifespan relative to non-obese controls in the NIA monkey cohort.

 

We saw in this study (PMID 25362635; discussed here), BAT-thermogenesis (resulting from cold exposure) may be necessary for the CR longevity benefits observed in rodents. Could the same be the case in monkeys? In other words, could the failure of CR to extend monkey lifespan have resulted from a failure to combine CR with cold exposure? It looks like a definite possibility.

 

From the full text of study [1], which specifies the details of the NIA monkey housing conditions:

 

The vivaria [where monkeys were housed] provided artificial lighting, maintained on a 12–12 LD cycle with lights on at 06:00. Room temperature (22–28 °C) and humidity (50–60%) were under automatic control.

 

So the ambient temperature of the NIA monkey environment ranged from 72 to 82 °F during the course of each day, which is on average is a little higher than thermal neutrality for rhesus monkeys, which appears to be around 75 °F [2]. This is also a lot higher than the constant 72 °F which is typical for CR rodent experiments, despite the fact that the thermal neutrality is higher for rodents than monkeys (and people).

 

Interestingly [1] also points out that after a while the CR monkeys didn't eat all that much, and weren't very motivated by food. This suggests to me they acclimated to their balmy housing conditions, and without the need for thermogenesis to keep warm, they downregulated their calorie needs. As a result, they ate less, but didn't live any longer...

 

So just like the study that showed CR didn't work when rodents were housed at or above thermally neutral conditions (PMID 25362635), the NIA monkey study showed CR didn't work in monkeys when there were housed at thermally neutral conditions. Unfortunately there wasn't (and likely never will be) a study of lifelong CR in monkeys housed in cool conditions...

 

But even without the "smoking gun" showing that CR+cold exposure extends lifespan in monkeys, the failure of CR to extend monkey lifespan under thermally neutral conditions seems like more suggestive evidence that if CR is to have a hope of working in humans it likely needs to be combined with cold exposure...

 

--Dean

 

----------

[1] Neurobiol Aging. 2005 Jul;26(7):1117-27. Epub 2004 Dec 10.

 

Age-related decline in caloric intake and motivation for food in rhesus monkeys.

 

Mattison JA(1), Black A, Huck J, Moscrip T, Handy A, Tilmont E, Roth GS, Lane MA,

Ingram DK.

 

Author information: 

(1)Laboratory of Cardiovascular Science, Gerontology Research Center, National

Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive,

Baltimore, MD 21224, USA.

 

Full text: http://gen.lib.rus.e...3&downloadname=

 

Human studies have documented age-related declines in caloric intake that are

pronounced at advanced ages. We examined caloric intake from a longitudinal study

of aging in 60 male and 60 female rhesus monkeys (Macaca mulatta) collected for

up to 10 years. Monkeys were provided a standardized, nutritionally fortified

diet during two daily meals, and intake was measured quarterly. About half of the

monkeys were on a regimen of caloric restriction (CR) representing about a 30%

reduction in caloric intake compared to controls (CON) of comparable age and body

weight. CR was applied to determine if this nutritional intervention retards the 

rate of aging in monkeys similar to observations in other mammalian studies.

Following reproductive maturity at 6 years of age, there was a consistent

age-related decline in caloric intake in these monkeys. Although males had higher

intake than females, and CON had higher intake compared to CR, the sex and diet

differences converged at older ages (>20 years); thus, older CR monkeys were no

longer consuming 30% less than the CON. When adjusted for body weight, an

age-related decline in caloric intake was still evident; however, females had

higher intake compared to males while CR monkeys still consumed less food, and

again differences converged at older ages. Motivation for food was assessed in 65

of the monkeys following at least 8 years in their respective diet groups. Using 

an apparatus attached to the home cage, following an overnight fast, monkeys were

trained to reach out of their cage to retrieve a biscuit of their diet by pushing

open a clear plastic door on the apparatus. The door was then locked, and thus

the biscuit was irretrievable. The time spent trying to retrieve the biscuit was 

recorded as a measure of motivation for food. We observed an age-related decline 

in this measure, but found no consistent differences in retrieval time between CR

and CON groups of comparable age and time on diet. The results demonstrate an

age-related decline in food intake and motivation for food in rhesus monkeys

paralleling findings in humans; however, we found no evidence that monkeys on a

long-term CR regimen were more motivated for food compared to CON. Examining the 

relationship of selected blood proteins to food intake following 7-11 years on

the study, we found a negative correlation between globulin and intake among

males and females after accounting for differences in age. In addition, a

positive correlation was observed between leptin and intake in males.

 

PMID: 15748792

 

----------

[2] Elizondo, R. S. (1988), Primate models to study eccrine sweating. Am. J. Primatol., 14: 265–276. doi: 10.1002/ajp.1350140307 

[drewab]

Possibly relevant to this thread:

 

I am wondering what effect exercising in the cold has?  I don't like the idea of subjecting myself to cold, just because it's uncomfortable, yet there have been many times in my life where I've gone for long runs in -30'C, or have run in 0'C in shorts and a t-shirt.  I find this to not only be tolerable, yet enjoyable.  This is some irony that since starting CR I often do find myself cold, and just suck it up and live with it.  

 

I feel that there is something that occurs when exercising under cold conditions that leads to a mild-moderate euphoric feeling.  I'm not sure if it's the release of dopamine, norepinephrine, or something else?  Dr. Rhonda Patrick recently touched it in on her podcast on cryotherapy.  (Her podcast is called Found My Fitness, and the one on cryotherapy is most recent in the list).

[Dean Pomerleau]

Drew,

 

I'll address your question about exercise, cold & BAT in my next post, since that is a pretty big topic. In researching it, I came across this study [1], which adds one more intervention to the list of BAT-activity inducers - fasting. 

 

The researchers in [1] first screened 10 healthy young men for BAT using the standard labelled PET imaging method. They found 6 out of 10 of them had detectable amounts of BAT when exposed to mild cold conditions (62.5 °F for 2 hours). In those six, the standard measure of BAT activity was twice as high in response to mild cold exposure when they were in a fasted state relative to the postprandial state (i.e. after eating "a chicken–bacon sandwich and 200 mL of whole milk (545 kcal)"). Two important things to note about this results though. First, the subjects (obviously) had to have BAT to begin with for fasting to increase its activity. This doesn't doesn't provide evidence one way or the other about whether fasting actual causes the body to make more BAT. Second, the greater increase in BAT activity when fasting relative to after eating was predicated on cold exposure to induce BAT activity in the first place. Simply fasting in warm conditions is unlikely to promote much if any BAT activity.

 

While it is a bit controversial, fasting is yet another BAT-inducing intervention that has long been thought by many to promote health and possibly longevity. The link between fasting and elevated BAT activity is yet more evidence suggesting BAT may play an important causal role in manifesting the benefits of many health-promoting practices & interventions.

 

Here is the latest full list of modifiable and [non-modifiable] factors associated with increased BAT quantity and/or activity:

• Cold exposure - by far the best BAT inducer/activator
• Metformin
• Green tea
• Caffeine
• Capsaicin
• Curcumin
• Fasting
• Low protein diet
• Avoid obesity/overweight
• Exercise
• [Being naturally thin - high metabolic rate]
• [Being younger]
• [Being female]
• [Ethnicity - having cold-climate ancestors]

 

--Dean

 

---------

[1] J Nucl Med. 2012 Sep;53(9):1407-10. doi: 10.2967/jnumed.111.100701. Epub 2012 Jul

31.

Fasting and postprandial activity of brown adipose tissue in healthy men.

Vrieze A(1), Schopman JE, Admiraal WM, Soeters MR, Nieuwdorp M, Verberne HJ,
Holleman F.

Author information:
(1)Department of Internal Medicine, Academic Medical Center, Amsterdam, The
Netherlands. a.vrieze@amc.uva.nl

 

Free full text: http://jnm.snmjourna.../53/9/1407.long

The role of brown adipose tissue (BAT) in adult metabolism is poorly understood.
This study aimed to examine the differential effects of an overnight fast and the
postprandial state on BAT activity.METHODS: We included 10 healthy, lean male
volunteers. BAT uptake of glucose was visualized using (18)F-FDG PET/CT during
mild cold exposure. Each subject underwent PET/CT twice. The first scan was
obtained after an overnight fast; the second after a standardized meal.
RESULTS: (18)F-FDG uptake in BAT was observed in 6 of 10 volunteers. These
subjects were found to have a higher maximal standardized uptake value when
fasting (median, 13.1 g/mL; range, 6.1-27.6 g/mL) than when in the postprandial
state (median, 6.8 g/mL; range, 2.1-13.4 g/mL) (P = 0.03).
CONCLUSION: Cold-stimulated (18)F-FDG uptake by BAT in humans is more pronounced
during fasting. The lower maximal standardized uptake value in the postprandial
state may be explained by increased insulin-stimulated glucose uptake in muscle.

PMID: 22851631

[Dean Pomerleau]

Drew,

 

Back to your question about exercising in the cold. First, since I engage in nearly continuous, low-intensity exercise during the day, most of my cold exposure is paired with mild exercise. I too find cold to be much more tolerable (bordering on pleasant) when I'm active vs. sedentary. Whether exercising during cold exposure will attenuate or potentiate BAT creation/activation is not entirely clear. As discussed in this post, this study (PMID 24506871) found that endurance exercise results in the 'browning' of white adipose tissue, but via a different pathway than cold exposure (Irisin vs. FGF21). Here is the graphical abstract from PMID 24506871 showing the two different pathways:

 

 

But in contrast, this study [1], found that endurance trained young male athletes had lower BAT activity in response to cold exposure than lean, sedentary young men. It also found that while the precursor to Irisin (FNDC5) was elevated in athletes, Irisin itself was no different between the athletes and the couch potatoes, in apparent contradiction to the study above which found exercise increased Irisin which in turn converted WAT to BAT. So it appears the jury is still out on whether exercise really does increase BAT.

 

Regarding the effects of exercising in the cold on mood and the feeling of 'euphoria'. Obviously exercise is well documented to improve mood through release of the neurotransmitters serotonin, dopamine and endorphins.  In contrast, the neurotransmitter norepinephrine (NE - also called noradrenalin) is the signalling molecule the brain & sympathetic nervous system uses to increase BAT activity in response to cold. I didn't know this, but low NE is also implicated in mood disorders & depression [2]. Interestingly, cocaine is a NE reuptake inhibitor, although it's thought to have its main impact via dopamine. Interestingly, sometimes people suffering from depression who don't respond to serotonin reuptake inhibitors are prescribed norepinephrine reuptake inhibitors to treat their depression.

 

So in short it is definitely conceivable that the combination of exercise and cold exposure could have additive positive psychological effects due to the different mood-boosting neurotransmitters they influence.

 

--Dean

 

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

[1]  Int J Obes (Lond). 2015 Dec;39(12):1696-702. doi: 10.1038/ijo.2015.130. Epub 2015

Jul 20.

 

Low brown adipose tissue activity in endurance-trained compared with lean

sedentary men.

 

Vosselman MJ(1), Hoeks J(1), Brans B(2), Pallubinsky H(1), Nascimento EB(1), van 

der Lans AA(1), Broeders EP(1), Mottaghy FM(2), Schrauwen P(1), van Marken

Lichtenbelt WD(1).

 

Author information: 

(1)Department of Human Biology, NUTRIM School of Nutrition and Translational

Research in Metabolism, Maastricht University Medical Center, Maastricht, The

Netherlands. (2)Department of Nuclear Medicine, Maastricht University Medical

Center, Maastricht, The Netherlands.

 

BACKGROUND/OBJECTIVES: It has now been unequivocally demonstrated that humans

possess functional brown adipose tissue (BAT) and that human BAT can be recruited

upon chronic cold stimulation. Recruitment of BAT has been postulated as a

potential strategy to counteract the current global obesity epidemic. Recently,

it was shown in rodents that endurance exercise training could stimulate the

recruitment of brown-like adipocytes within white adipose tissue (WAT) via

exercise-induced myokines such as irisin (the cleaved circulating product of the 

type 1 membrane protein FNDC5) and interleukin-6 (IL-6). Our objective was to

test whether endurance-trained athletes had increased cold-stimulated BAT

activity and browning of subcutaneous WAT compared with lean sedentary males.

SUBJECTS/METHODS: Twelve endurance-trained athletes and 12 lean sedentary males

were measured during 2 h of mild cold exposure to determine cold-induced BAT

activity via [(18)F]fluorodeoxyglucose-positron emission tomography-computed

tomography ([(18)F]FDG-PET-CT) scanning. Skeletal muscle FNDC5 expression, as

well as plasma irisin and IL-6 levels were determined. In addition, a

subcutaneous abdominal WAT biopsy was taken to measure gene expression of several

markers for browning of WAT.

RESULTS: Cold-induced BAT activity was significantly lower in athletes, and no

differences in gene expression of classical brown and beige adipocyte markers

were detected in subcutaneous WAT between the groups. As expected, mRNA

expression of FNDC5 in skeletal muscle was significantly higher in endurance

athletes but plasma irisin and Il-6 levels were similar in both groups.

CONCLUSIONS: These results indicate that chronic endurance exercise is not

associated with brown and beige adipocyte recruitment; in fact endurance training

appears to be linked to lower the metabolic activity of BAT in humans.

 

PMID: 26189600

 

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

[2] Neuropsychiatr Dis Treat. 2011;7(Suppl 1):9-13. doi: 10.2147/NDT.S19619. Epub

2011 May 31.

 

The importance of norepinephrine in depression.

 

Moret C(1), Briley M.

 

Author information: 

(1)NeuroBiz Consulting and Communication, Castres, France.

 

Free full text: http://www.ncbi.nlm....les/PMC3131098/

 

Depression is one of the most common psychological diseases with significant

potential morbidity and mortality. Although the underlying pathophysiology of

depression has not been clearly defined, preclinical and clinical evidence

suggest disturbances in serotonin (5-HT), norepinephrine (NE), and dopamine (DA) 

neurotransmission in the central nervous system. Virtually all currently

available antidepressants act on one or more of the following mechanisms:

inhibition of reuptake of 5-HT or NE (and DA), antagonism of inhibitory

presynaptic 5-HT or NE receptors, or inhibition of monoamine oxidase. All of

these mechanisms result in an enhanced neurotransmission of 5-HT and/or NE.

Evidence for the involvement of NE in depression is abundant, and recent studies 

on neuronal pathways and symptoms highlight the specific role of NE in this

disorder. NE plays a determinant role in executive functioning regulating

cognition, motivation, and intellect, which are fundamental in social

relationships. Social dysfunction is possibly one of the most important factors

affecting the quality of life in depressed patients.

 

PMCID: PMC3131098

PMID: 21750623

[Dean Pomerleau]

Ok, I promise this will be my past BAT-related post for the day - but don't worry I've got a couple more in the pipeline for tomorrow :-)

 

In my continuing quest to discover new methods for stimulating BAT synthesis / activation, I came across new candidates in the full text of [1], which contained this diagram:

 

 

 

As you can see at the top of the diagram both cold exposure and "food ingredients" signal the sympathetic nervous system via a family of "transient receptor potential" channels ((TRPs) to release norepinephrine which activates white, beige and brown adipose cells to burn fat. The discussion in [1] of the "food ingredients" that activate TRPs is the following: 

 

Actually, there are various ingredients in food acting as agonists for these TRPs [2], a representative of which is menthol, a cooling and flavor compound in mint, acting on TRPM8. TRPA1 is activated by allyl- and benzyl-isothiocyanates, pungent elements in mustard and Wasabi (Japanese horseradish). Among the TRP agonists, the most extensively studied is capsaicin, a pungent principle of chili pepper, which is a potent agonist for TRPV1.

 

So methol/mint, mustard & horseradish can be added to capsaicin/chilli and curcumin/turmeric as food ingredients that trigger BAT activity (although again, not necessarily new BAT synthesis). And tracking down reference [2], I found a couple more. Here are excerpts from the full text of [2] : 

 

TRPV3 [another member of the TRP family] can alternatively be activated by camphor (92), irritant extracts from oregano and cloves (161)...

 

TRPM8 [another member of the TRP family]  as an ion channel that could be activated by either menthol or cool temperatures....

 

Support for a functional role of TRPA1 [another member of the TRP family] in nociceptive neurons has come from the demonstration that pungent chemical ligands, including isothiocyanates such as those found in mustard oil, wasabi, and garlic, as well as other irritant chemicals such as acrolein, are capable of activating this channel (6, 9, 69).

 

I'd never heard of acrolein before, so I looked it up. It turns out it's present in a number of foods that many of us consider healthy, along with some unhealthy ones as well. From this CDC document:

 

Acrolein is also present in certain foods such as raw cocoa beans, chocolate liquor, fried potatoes and onions, raw and cooked turkey, heated animal fats and vegetable oils, and roasted coffee.

 

All these new foods would greatly expand my list of BAT inducers, even if we eliminate the fried potatoes & animal products due to their other health downsides. So I'm going to do some consolidation to the list.

 

Here is the latest full list of modifiable and [non-modifiable] factors associated with increased BAT quantity and/or activity:

• Cold exposure - by far the best BAT inducer/activator
• Spicy / pungent foods, herbs & supplements - capsaicin / chilli peppers, curcumin / turmeric root, menthol/mint/camphor, oregano, cloves, mustard, horseradish/wasabi, garlic, onions
• Other foods - green tea, roasted coffee, cacao beans / chocolate
• Drugs - metformin, caffeine
• Exercise
• Fasting
• Low protein diet
• Avoid obesity/overweight
• [Being naturally thin - high metabolic rate]
• [Being younger]
• [Being female]
• [Ethnicity - having cold-climate ancestors]

This list of BAT inducers is looking more and more like a "who's who" list of the best known foods & lifestyle choices for health and longevity. It's pretty amazing, and perhaps not coincidental, that they all have been shown to increase BAT activity...

 

--Dean

 

-----------

[1] Diabetes Metab J. 2013 Feb;37(1):22-9. doi: 10.4093/dmj.2013.37.1.22. Epub 2013

Feb 15.

 

Brown adipose tissue as a regulator of energy expenditure and body fat in humans.

 

Saito M(1).

 

Author information: 

(1)Department of Nutrition, Tenshi College, Sapporo, Japan.

 

Free full text: http://www.e-dmj.org...vmode=PUBREADER

 

Brown adipose tissue (BAT) is recognized as the major site of sympathetically

activated nonshivering thermogenesis during cold exposure and after spontaneous

hyperphagia, thereby controling whole-body energy expenditure and body fat. In

adult humans, BAT has long been believed to be absent or negligible, but recent

studies using fluorodeoxyglucose-positron emission tomography, in combination

with computed tomography, demonstrated the existence of metabolically active BAT 

in healthy adult humans. Human BAT is activated by acute cold exposure, being

positively correlated to cold-induced increases in energy expenditure. The

metabolic activity of BAT differs among individuals, being lower in older and

obese individuals. Thus, BAT is recognized as a regulator of whole-body energy

expenditure and body fat in humans as in small rodents, and a hopeful target

combating obesity and related disorders. In fact, there are some food ingredients

such as capsaicin and capsinoids, which have potential to activate and recruit

BAT via activity on the specific receptor, transient receptor potential channels,

thereby increasing energy expenditure and decreasing body fat modestly and

consistently.

 

PMCID: PMC3579148

PMID: 23441053

 

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

[2] Am J Physiol Regul Integr Comp Physiol. 2007 Jan;292(1):R64-76. Epub 2006 Sep 14.

 

Transient receptor potential ion channels as participants in thermosensation and 

thermoregulation.

 

Caterina MJ(1).

 

Author information: 

(1)Department of Biological Chemistry, Center for Sensory Biology, Johns Hopkins 

School of Medicine, 725 N. Wolfe St., Baltimore, MD 21205, USA. caterina@jhmi.edu

 

Free full text: http://ajpregu.physi.../292/1/R64.long

 

Living organisms must evaluate changes in environmental and internal temperatures

to mount appropriate physiological and behavioral responses conducive to

survival. Classical physiology has provided a wealth of information regarding the

specialization of thermosensory functions among subclasses of peripheral sensory 

neurons and intrinsically thermosensitive neurons within the hypothalamus.

However, until recently, the molecular mechanisms by which these cells carry out 

thermometry have remained poorly understood. The demonstration that certain ion

channels of the transient receptor potential (TRP) family can be activated by

increases or decreases in ambient temperature, along with the recognition of

their heterogeneous expression patterns and heterogeneous temperature

sensitivities, has led investigators to evaluate these proteins as candidate

endogenous thermosensors. Much of this work has involved one specific channel,

TRP vanilloid 1 (TRPV1), which is both a receptor for capsaicin and related

pungent vanilloid compounds and a "heat receptor," capable of directly

depolarizing neurons in response to temperatures >42 degrees C. Evidence for a

contribution of TRPV1 to peripheral thermosensation has come from

pharmacological, physiological, and genetic approaches. In contrast, although

capsaicin-sensitive mechanisms clearly influence core body temperature

regulation, the specific contribution of TRPV1 to this process remains a matter

of debate. Besides TRPV1, at least six additional thermally sensitive TRP

channels have been identified in mammals, and many of these also appear to

participate in thermosensation. Moreover, the identification of invertebrate TRP 

channels, whose genetic ablation alters thermally driven behaviors, makes it

clear that thermosensation represents an evolutionarily conserved role of this

ion channel family.

 

PMID: 16973931

[AlPater]

Brown adipose tissue's roles in energy metabolism and aging are further studied in the below paper.

 

 

Dicer1-miR-328-Bace1 signalling controls brown adipose tissue differentiation and function.
Oliverio M, Schmidt E, Mauer J, Baitzel C, Hansmeier N, Khani S, Konieczka S, Pradas-Juni M, Brodesser S, Van TM, Bartsch D, Brönneke HS, Heine M, Hilpert H, Tarcitano E, Garinis GA, Frommolt P, Heeren J, Mori MA, Brüning JC, Kornfeld JW.
Nat Cell Biol. 2016 Mar;18(3):328-36. doi: 10.1038/ncb3316. Epub 2016 Feb 22.
PMID: 26900752

 

Abstract

 

Activation of brown adipose tissue (BAT) controls energy homeostasis in rodents and humans and has emerged as an innovative strategy for the treatment of obesity and type 2 diabetes mellitus. Here we show that ageing- and obesity-associated dysfunction of brown fat coincides with global microRNA downregulation due to reduced expression of the microRNA-processing node Dicer1. Consequently, heterozygosity of Dicer1 in BAT aggravated diet-induced-obesity (DIO)-evoked deterioration of glucose metabolism. Analyses of differential microRNA expression during preadipocyte commitment and mouse models of progeria, longevity and DIO identified miR-328 as a regulator of BAT differentiation. Reducing miR-328 blocked preadipocyte commitment, whereas miR-328 overexpression instigated BAT differentiation and impaired muscle progenitor commitment-partly through silencing of the β-secretase Bace1. Loss of Bace1 enhanced brown preadipocyte specification in vitro and was overexpressed in BAT of obese and progeroid mice. In vivo Bace1 inhibition delayed DIO-induced weight gain and improved glucose tolerance and insulin sensitivity. These experiments reveal Dicer1-miR-328-Bace1 signalling as a determinant of BAT function, and highlight the potential of Bace1 inhibition as a therapeutic approach to improve not only neurodegenerative diseases but also ageing- and obesity-associated impairments of BAT function.

-- Al Pater, alpater@SHAW.ca

[drewab]

Dean - thanks for taking the time to look into this. It's funny how the same thing (increasing BAT) can be accomplished via so many different foods/mechanisms. I also believe it's no coincidence that some of these foods that do us well through other mechanisms also apparently have a BAT mechanism too. It's a little ironic that chilli peppers contribute to BAT, though they make me sweat so much!

[Dean Pomerleau]

Drew,

One of the reasons chilli peppers make you sweat is that they induce thermogenesis in BAT, causing your actually be hotter. Your body sweats to compensate. Dr. Greger has a video (embedded below) on how to boost brown fat thermogenesis besides cold exposure. In it, he talks about a study [1] which found hot peppers increase metabolic rate, but only in people with measureable brown fat. Here is the figure showing the differential response of resting energy expenditure in BAT-positive and BAT-negative men, during the two hours after ingestion of either capsaicin or a placebo while hanging out in warm conditions (81 °F):

 

 

The capsaicin raised metabolic rate by about 120kcal/day, but only in the group of men who had measurable BAT. So it definitely looks like part of the 'burn' (bern? :-)) you feel as a result of eating chilli peppers is literally more heat generated by BAT. Interestingly, in another paper by these same researchers [2], they found that after six weeks of daily ingestion of capsaicin the group who initially had no measurable BAT displayed "a slight but significant increase in cold-induced thermogenesis – an index of BAT activity – in individuals given capsinoids daily for 6 weeks."

 

So hot peppers may not only activate existing BAT, but also chronic ingestion of capsaicin may (slightly) increase the amount of BAT you have.

 

--Dean

 

 

P.S. For anyone who wants a quick primer on BAT in humans, Dr. Greger has a good introductory video:

 

 

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

[1] Curr Opin Lipidol. 2013 Feb;24(1):71-7. doi: 10.1097/MOL.0b013e32835a4f40.

Capsinoids and related food ingredients activating brown fat thermogenesis and
reducing body fat in humans.

Saito M(1), Yoneshiro T.

Author information:
(1)Department of Nutrition, Tenshi College, Sapporo, Japan. saito@tenshi.ac.jp

 

Full text: http://sci-hub.io/10...b013e32835a4f40

PURPOSE OF REVIEW: Capsaicin and its nonpungent analog (capsinoids) are known to
be food ingredients that increase energy expenditure and decrease body fat. This
article reviews the role of brown adipose tissue (BAT) for the thermogenic effect
of these compounds in humans and proposes the possibility of some other
antiobesity food ingredients.
RECENT FINDINGS: A single oral ingestion of capsinoids increases energy
expenditure in human individuals with metabolically active BAT, but not those
without it, indicating that capsinoids activate BAT and thereby increase energy
expenditure. This finding gave a rational explanation for discrepant results of
the effects of capsinoids in the previous studies. Human BAT may be largely
composed of inducible 'beige' adipocytes more than typical brown adipocytes
because its gene expression patterns are similar to beige cells isolated from
murine white fat depots. In fact, preadipocytes isolated from supraclavicular fat
deposits - where BAT is often detected - are capable of differentiating into
brown-like adipocytes in vitro, providing evidence of inducible brown
adipogenesis in adult humans.
SUMMARY: As human BAT may be inducible, a prolonged ingestion of capsinoids would
recruit active BAT and thereby increase energy expenditure and decrease body fat.
In addition to capsinoids, there are numerous food ingredients that are expected
to activate BAT and so be useful for the prevention of obesity in daily life.

PMID: 23298960

 

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

[2] The FASEB Journal. 2012;26:252.4

 

Activation of brown adipose tissue by acute and chronic administrations of capsinoids in humans

 

Takeshi Yoneshiro1, Sayuri Aita2, Mami Matsushita2 and Masayuki Saito2

 

1 Laboratory of Histology and Cytology, Department of Anatomy, Hokkaido University Graduate School of Medicine, Sapporo, Japan

2 Department of Nutrition, School of Nursing and Nutrition, Tenshi College, Sapporo, Japan

 

Objective: Capsinoids, nonpungent capsaicin-related substances, are known to increase brown adipose tissue (BAT) thermogenesis and whole-body energy expenditure (EE), and reduce body fat in small rodents. The objective of this study was to clarify whether BAT is involved in the thermogenic effects of capsinoids in humans.

 

Results: Eighteen male volunteers underwent fluorodeoxyglucose- positron emission tomography after 2-h cold exposure at 19 °C, and were divided into BAT-positive and - negative groups. Thermogenic responses to orally ingested capsinoids (9mg) or placebo were examined by indirect calorimetry at 27 °C. Thermogenic responses to cold at 19 °C (CIT) were also examined before and after daily ingestion of capsinoids for 6 weeks.

 

Results: Oral ingestion of capsinoids increased EE in 1 h by 15.2 ± 2.6 kJ/h in the BAT-positive group, more than in the BAT-negative group (1.7 ± 3.8 kJ/h). Placebo ingestion produced no significant change in either group. CIT in the BAT-negative group was much lower than that in the BAT-positive group, but it increased after 6-week capsinoids ingestion.

 

Conclutions: Oral ingestion of capsinoids increases EE by stimulating and recruiting BAT in humans.

[Dean Pomerleau]

Here is another one for the list - foods rich in the amino acid L-arginine. This review [1], cites a number of studies in which supplementing the diet of rodents with L-arginine increased BAT. One good one is [2], which had four groups of mice, fed either a normal diet with or without extra arginine or obesity-inducing high-fat diet with or without extra arginine. At the end of 15 weeks, both arginine groups has about 35% more BAT than their respective control groups, and had gained less weight despite eating identical amounts of food!

 

So what foods are rich in arginine? Lots of high protein animal products. On the vegan side, seeds (esp. sesame, sunflower & pumpkin seeds), nuts (esp. almonds and walnuts) and legumes (esp. soy beans, lupin beans (Saul!), fava beans and peas). I'm going add arginine although with these vegan arginine-rich foods to the list.

 

Here is the latest full list of modifiable and [non-modifiable] factors associated with increased BAT quantity and/or activity:

• Cold exposure - by far the best BAT inducer/activator
• Spicy / pungent foods, herbs & supplements - capsaicin / chilli peppers, curcumin / turmeric root, menthol/mint/camphor, oregano, cloves, mustard, horseradish/wasabi, garlic, onions
• Arginine-rich foods - Good vegan sources include seeds (esp. sesame, sunflower & pumpkin), nuts (esp. almonds and walnuts) and legumes (esp. soy, lupin & fava beans and peas)
• Other foods - green tea, roasted coffee, cacao beans / chocolate
• Drugs - metformin, caffeine
• Exercise
• Fasting
• Low protein diet
• Avoid obesity/overweight
• [Being naturally thin - high metabolic rate]
• [Being younger]
• [Being female]
• [Ethnicity - having cold-climate ancestors]

 

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

[1] Curr Opin Clin Nutr Metab Care. 2012 Nov;15(6):529-38. doi:

10.1097/MCO.0b013e3283595cff.

Regulation of brown adipose tissue development and white fat reduction by
L-arginine.

Wu Z(1), Satterfield MC, Bazer FW, Wu G.

Author information:
(1)State Key Laboratory of Animal Nutrition, College of Animal Science and
Technology, China Agricultural University, Beijing, China.

 

full text: http://sci-hub.io/10...b013e3283595cff

PURPOSE OF REVIEW: Brown adipose tissue (BAT), which is present in humans, plays
an important role in oxidation of fatty acids and glucose. The purpose of this
review is to highlight an important role for L-arginine in regulating BAT growth
and development, thereby reducing obesity in mammals.
RECENT FINDINGS: Dietary supplementation with L-arginine reduces white adipose
tissue in genetically or diet-induced obese rats, obese pregnant sheep, and obese
humans with type II diabetes. L-arginine treatment enhances BAT growth in both
fetuses and postnatal animals. At molecular and cellular levels, L-arginine
stimulates expression of peroxisome proliferator-activated receptor-γ coactivator
1 (the master regulator of mitochondrial biogenesis), nitric oxide synthase, heme
oxygenase, and adenosine monophosphate-activated protein kinase. At the whole
body level, L-arginine increases blood flow to insulin-sensitive tissues, adipose
tissue lipolysis, and the catabolism of glucose and fatty acids, but inhibits
fatty acid synthesis and ameliorates oxidative stress, thereby improving
metabolic profile.
SUMMARY: L-arginine increases mammalian BAT growth and development via mechanisms
involving gene expression, nitric oxide signaling, and protein synthesis. This
enhances the oxidation of energy substrates and, thus, reduces white fat
accretion in the body. L-arginine holds great promise in preventing and treating
obesity in humans.

PMID: 23075933 

 

---------

[2] J Nutr. 2009 Feb;139(2):230-7. doi: 10.3945/jn.108.096362. Epub 2008 Dec 23.

Dietary L-arginine supplementation reduces white fat gain and enhances skeletal
muscle and brown fat masses in diet-induced obese rats.

Jobgen W(1), Meininger CJ, Jobgen SC, Li P, Lee MJ, Smith SB, Spencer TE, Fried
SK, Wu G.

Author information:
(1)Department of Animal Science, Faculty of Nutrition, Texas A&M University,
College Station, TX 77843, USA.

 

Free full text: http://www.ncbi.nlm....les/PMC3151442/

Previous studies showed that dietary L-arginine supplementation decreased white
fat mass in genetically obese rats. This study tested the effectiveness of
L-arginine in diet-induced obesity. Male Sprague-Dawley rats were fed for 15 wk a
high-fat (HF) (40% energy) or low-fat (LF) (10% energy) diet beginning at 4 wk of
age, resulting in 18% higher body weight gains and 74% higher weights of major
white fat pads (retroperitoneal, epididymal, subcutaneous, and mesenteric adipose
tissues) in HF than in LF fed rats. Starting at 19 wk of age, rats in each
dietary group were supplemented for 12 wk with 1.51% L-arginine-HCl or 2.55%
L-alanine (isonitrogenous control) (n = 8 per treatment) in drinking water and
arginine groups were individually pair-fed to alanine controls. Despite similar
energy intake, absolute weights of white fat pads increased by 98% in control
rats over a 12-wk period but only by 35% in arginine-supplemented rats. The
arginine treatment reduced the relative weights of white fat pads by 30% and
enhanced those of soleus muscle by 13%, extensor digitorum longus muscle by 11%,
and brown fat by 34% compared with control rats. Serum concentrations of insulin,
adiponectin, growth hormone, corticosterone, triiodothyronine, and thyroxine did
not differ between control and arginine-supplemented rats. However, arginine
treatment resulted in lower serum concentrations of leptin, glucose,
triglycerides, urea, glutamine, and branched-chain amino acids, higher serum
concentrations of nitric-oxide metabolites, and improvement in glucose tolerance.
Thus, dietary arginine supplementation shifts nutrient partitioning to promote
muscle over fat gain and may provide a useful treatment for improving the
metabolic profile and reducing body white fat in diet-induced obese rats.

PMCID: PMC3151442
PMID: 19106310

[Dean Pomerleau]

All,

 

In this post discussing PMID 3668686, it's clear that a diet that is overall low in protein promotes BAT. Here is another study [1] showing even more directly that a low-protein diet stimulates BAT activity and energy expenditure. In my last post, I pointed to evidence that the amino acid arginine appear to boost the amount of brown fat activity.  But what about the mother of all protein-related, longevity-promoting dietary interventions - methionine restriction (MR)? Could the benefits of MR have something to do with BAT? Let's find out...

 

The two most cited studies documenting the longevity benefits of MR are this study [2] of rats and this study [3] of mice. Below are the survival curves of MR rats (left) and mice (right) from the two studies:

 

In rats, MR resulted in an mean lifespan extension of 20%, and a maximum lifespan extension of 12%. In fact, MR is one of the very few interventions that has ever been shown to increase max-lifespan. A fact I didn't know is that the MR rats ate more calories (after normalizing for body weight), but weighed less, than controls. Here is the body weight (left), absolute food intake (middle) and BW-normalized food intake (right) for MR rats (triangles) vs. control rats (circles). 

 

 

As you can see, the MR rats gained no weight, and weighed significantly less than the control rats, despite eating nearly as much absolutely, and significantly more than controls once adjusted for body weight. The mice in [3] were similar in this regard to the rats in [2]. Namely:

 

Mice given the control diet consumed an average of 3.8 ± 0.7 g day−1 (mean ± SD), as compared with 4.3 ± 1.1 g day−1 for mice receiving the [methionine-] restricted diet. These data provide no evidence for the idea that the low-methionine food is less palatable than the control diet. ... the data are consistent with previous reports, from rat studies, that animals on the low-methionine diet consume at least as much food per gram body weight as controls.

 

Despite consuming more food, the MR mice in [3] also weighed significantly less than controls as you can see from this diagram:

 

 

 

Hmmm.... increased food consumption without weight gain, resulting in increased longevity. You should know by now where this is headed...

 

Yup - you guessed it. Methionine restriction is yet one more way to increase BAT, as evidenced by [4] and [5]. Focusing on [5], researchers studied MR rats vs. controls. Again the MR rats ate more for their size, but weighed less than controls. The MR rats were not thinner because of increased voluntary activity:

 

[There was] no evidence that the higher [energy expenditure] in MR rats was attributable to increased voluntary activity at night. In addition, ambulatory activity of the MR group during the day was significantly lower than that of the control group.

 

But the MR mice did have a higher core body temperature (by about 2°F!) which explains their increased energy expenditure and their low weight despite eating more. And the cause of this increase in core body temperature in the MR rats? Increased BAT activity, as is evidenced by this graph of uncoupling protein-1 expression in BAT, a marker for BAT thermogenic activity :

 

 

In support of UCP1's importance in the metabolic impact of MR, study [7] of mice lacking UCP1 found:

 

MR increased [energy expenditure] by 31% and reduced adiposity by 25% in [normal] mice. In contrast, MR failed to increase [energy expenditure] or reduce adiposity in [UCP1-knockout] mice.

 

Interestingly, MR appears to 'work its magic' through increased expression of FGF21 [6]. This is interesting, because in this post we saw that mice genetically engineered to overexpress FGF21 ate more, weighed less, and live longer than control mice, just like the MR mice. And we've also seen cold exposure elevates FGF21 in rodents and people (PMID: 23150685). So it appears MR and cold exposure have similar influences on the body, and both act through upregulation of FGF21.

 

In summary, a (perhaps the) major physiological change resulting from methionine restriction is an increase in BAT activity via UCP1, which results in higher energy expenditure & food intake, but no increase in body weight. And of course, we know that methionine restriction results in increased lifespan. The evidence that methionine restriction promotes health and longevity via increased BAT activity would seem to put to rest any lingering doubts anyone might still harbor about the potential benefits of BAT and cold exposure.

 

Here is the latest full list of modifiable and [non-modifiable] factors associated with increased BAT quantity and/or activity:

• Cold exposure - by far the best BAT inducer/activator
• Methionine restriction - Reduce animal protein. Soy is low in methionine and high in arginine (see below).
• Spicy / pungent foods, herbs & supplements - capsaicin / chilli peppers, curcumin / turmeric root, menthol/mint/camphor, oregano, cloves, mustard, horseradish/wasabi, garlic, onions
• Arginine-rich foods - Good vegan sources include seeds (esp. sesame, sunflower & pumpkin), nuts (esp. almonds and walnuts) and legumes (esp. soy, lupin & fava beans and peas)
• Other foods - green tea, roasted coffee, cacao beans / chocolate
• Drugs - metformin, caffeine
• Exercise
• Fasting
• Low protein diet
• Avoid obesity/overweight
• [Being naturally thin - high metabolic rate]
• [Being younger]
• [Being female]
• [Ethnicity - having cold-climate ancestors]

--Dean

 

--------

[1] Nutrition. 2009 Nov-Dec;25(11-12):1186-92. doi: 10.1016/j.nut.2009.03.011. Epub

2009 Jun 17.

 

Low protein diet changes the energetic balance and sympathetic activity in brown 

adipose tissue of growing rats.

 

Aparecida de França S(1), Dos Santos MP, Garófalo MA, Navegantes LC, Kettelhut

Ido C, Lopes CF, Kawashita NH.

 

Author information: 

(1)Department of Chemistry, Federal University of Mato Grosso, Cuiabá, Mato

Grosso, Brazil.

 

OBJECTIVE: The aim of this study was to assess the effects of protein restriction

in growing rats.

METHODS: Rats (approximate weight, 100g) were maintained with low-protein (LP;

6%) or normoproteic (control; 17%) diets, and at the end of the 15th day,

hormonal and biochemistry parameters and energetic balance were evaluated. Data

were analyzed using Student's t test (with statistical significance set at P < or

= .05).

RESULTS: LP animals were hyperphagic and showed increased energetic gain (24%)

and energy expenditure (EE) compared with controls. The increase in EE was

followed by increased sympathetic activity in brown adipose tissue, evidenced by 

increased norepinephrine turnover, suggesting increased thermogenesis. In spite

of hyperphagia, protein ingestion in LP animals was lower than that of controls

(P<0.01). The LP diet impaired body growth and caused deep alterations in body

chemical composition, with an increase in carcass lipid content (64%) and

reductions of protein and water. In LP animals, postprandial glycemia was

unchanged, and insulinemia was lower than in controls (P < or = .01). Reduction

in fasting glycemia without changes in insulinemia also was detected (P < .01),

suggesting increased insulin sensitivity. The LP diet caused a 100% increase in

serum leptin (P < .01).

CONCLUSIONS: Protein restriction led to an increase in EE, with probable

activation of thermogenesis in brown adipose tissue, evidenced by an increase in 

catecholamines levels. Despite the higher EE, energetic gain and lipids

increased. The high level of leptin associated with hyperphagia led to the

supposition that these animals are leptin resistant, and the increase in insulin 

sensitivity, suggested by the relation between insulin and glycemia in fasting

and fed animals, might contribute to lipid accumulation.

 

PMID: 19535223

 

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

[2] J Nutr. 1993 Feb;123(2):269-74.

 

Low methionine ingestion by rats extends life span.

 

Orentreich N(1), Matias JR, DeFelice A, Zimmerman JA.

 

Author information: 

(1)Orentreich Foundation for the Advancement of Science, Inc., Biomedical

Research Station, Cold Spring-on-Hudson, NY 10516.

 

 

Free full text: https://www.research...tends_Life_Span

 

 

Dietary energy restriction has been a widely used means of experimentally

extending mammalian life span. We report here that lifelong reduction in the

concentration of a single dietary component, the essential amino acid

L-methionine, from 0.86 to 0.17% of the diet results in a 30% longer life span of

male Fischer 344 rats. Methionine restriction completely abolished growth,

although food intake was actually greater on a body weight basis. Studies of

energy consumption in early life indicated that the energy intake of 0.17%

methionine-fed animals was near normal for animals of their size, although

consumption per animal was below that of the much larger 0.86% methionine-fed

rats. Increasing the energy intake of rats fed 0.17% methionine failed to

increase their rate of growth, whereas restricting 0.85% methionine-fed rats to

the food intake of 0.17% methionine-fed animals did not materially reduce growth,

indicating that food restriction was not a factor in life span extension in these

experiments. The biochemically well-defined pathways of methionine metabolism and

utilization offer the potential for uncovering the precise mechanism(s)

underlying this specific dietary restriction-related extension of life span.

 

PMID: 8429371

 

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

[3] Aging Cell. 2005 Jun;4(3):119-25.

 

Methionine-deficient diet extends mouse lifespan, slows immune and lens aging,

alters glucose, T4, IGF-I and insulin levels, and increases hepatocyte MIF levels

and stress resistance.

 

Miller RA(1), Buehner G, Chang Y, Harper JM, Sigler R, Smith-Wheelock M.

 

Author information: 

(1)Department of Pathology, Geriatrics Center, University of Michigan School of

Medicine, Ann Arbor, MI 48109-0940, USA. millerr@umich.edu

 

Free full text: http://onlinelibrary...05.00152.x/full

 

A diet deficient in the amino acid methionine has previously been shown to extend

lifespan in several stocks of inbred rats. We report here that a

methionine-deficient (Meth-R) diet also increases maximal lifespan in (BALB/cJ x 

C57BL/6 J)F1 mice. Compared with controls, Meth-R mice have significantly lower

levels of serum IGF-I, insulin, glucose and thyroid hormone. Meth-R mice also

have higher levels of liver mRNA for MIF (macrophage migration inhibition

factor), known to be higher in several other mouse models of extended longevity. 

Meth-R mice are significantly slower to develop lens turbidity and to show

age-related changes in T-cell subsets. They are also dramatically more resistant 

to oxidative liver cell injury induced by injection of toxic doses of

acetaminophen. The spectrum of terminal illnesses in the Meth-R group is similar 

to that seen in control mice. Studies of the cellular and molecular biology of

methionine-deprived mice may, in parallel to studies of calorie-restricted mice, 

provide insights into the way in which nutritional factors modulate longevity and

late-life illnesses.

 

PMID: 15924568

 

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

[4] Am J Physiol Regul Integr Comp Physiol. 2010 Sep;299(3):R740-50. doi:

10.1152/ajpregu.00838.2009. Epub 2010 Jun 16.

 

Role of beta-adrenergic receptors in the hyperphagic and hypermetabolic responses

to dietary methionine restriction.

 

Plaisance EP(1), Henagan TM, Echlin H, Boudreau A, Hill KL, Lenard NR, Hasek BE, 

Orentreich N, Gettys TW.

 

Author information: 

(1)Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical 

Research Center, Baton Rouge, Louisiana, USA.

 

Free full text: http://www.ncbi.nlm....les/PMC2944424/

 

Dietary methionine restriction (MR) limits fat deposition and decreases plasma

leptin, while increasing food consumption, total energy expenditure (EE), plasma 

adiponectin, and expression of uncoupling protein 1 (UCP1) in brown and white

adipose tissue (BAT and WAT). beta-adrenergic receptors (beta-AR) serve as

conduits for sympathetic input to adipose tissue, but their role in mediating the

effects of MR on energy homeostasis is unclear. Energy intake, weight, and

adiposity were modestly higher in beta(3)-AR(-/-) mice on the Control diet

compared with wild-type (WT) mice, but the hyperphagic response to the MR diet

and the reduction in fat deposition did not differ between the genotypes. The

absence of beta(3)-ARs also did not diminish the ability of MR to increase total 

EE and plasma adiponectin or decrease leptin mRNA, but it did block the

MR-dependent increase in UCP1 mRNA in BAT but not WAT. In a further study,

propranolol was used to antagonize remaining beta-adrenergic input (beta(1)- and 

beta(2)-ARs) in beta(3)-AR(-/-) mice, and this treatment blocked >50% of the

MR-induced increase in total EE and UCP1 induction in both BAT and WAT. We

conclude that signaling through beta-adrenergic receptors is a component of the

mechanism used by dietary MR to increase EE, and that beta(1)- and beta(2)-ARs

are able to substitute for beta(3)-ARs in mediating the effect of dietary MR on

EE. These findings are consistent with the involvement of both UCP1-dependent and

-independent mechanisms in the physiological responses affecting energy balance

that are produced by dietary MR.

 

PMCID: PMC2944424

PMID: 20554934

 

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

[5] Am J Physiol Regul Integr Comp Physiol. 2010 Sep;299(3):R728-39. doi:

10.1152/ajpregu.00837.2009. Epub 2010 Jun 10.

 

Dietary methionine restriction enhances metabolic flexibility and increases

uncoupled respiration in both fed and fasted states.

 

Hasek BE(1), Stewart LK, Henagan TM, Boudreau A, Lenard NR, Black C, Shin J,

Huypens P, Malloy VL, Plaisance EP, Krajcik RA, Orentreich N, Gettys TW.

 

Author information: 

(1)Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical 

Research Center, Baton Rouge, Louisiana, USA.

 

Free full text: http://www.ncbi.nlm....les/PMC2944433/

 

Dietary methionine restriction (MR) is a mimetic of chronic dietary restriction

(DR) in the sense that MR increases rodent longevity, but without food

restriction. We report here that MR also persistently increases total energy

expenditure (EE) and limits fat deposition despite increasing weight-specific

food consumption. In Fischer 344 (F344) rats consuming control or MR diets for 3,

9, and 20 mo, mean EE was 1.5-fold higher in MR vs. control rats, primarily due

to higher EE during the night at all ages. The day-to-night transition produced a

twofold higher heat increment of feeding (3.0 degrees C vs. 1.5 degrees C) in MR 

vs. controls and an exaggerated increase in respiratory quotient (RQ) to values

greater than 1, indicative of the interconversion of glucose to lipid by de novo 

lipogenesis. The simultaneous inhibition of glucose utilization and shift to fat 

oxidation during the day was also more complete in MR (RQ approximately 0.75) vs.

controls (RQ approximately 0.85). Dietary MR produced a rapid and persistent

increase in uncoupling protein 1 expression in brown (BAT) and white adipose

tissue (WAT) in conjunction with decreased leptin and increased adiponectin

levels in serum, suggesting that remodeling of the metabolic and endocrine

function of adipose tissue may have an important role in the overall increase in 

EE. We conclude that the hyperphagic response to dietary MR is matched to a

coordinated increase in uncoupled respiration, suggesting the engagement of a

nutrient-sensing mechanism, which compensates for limited methionine through

integrated effects on energy homeostasis.

 

PMCID: PMC2944433

PMID: 20538896

 

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

[6] Aging Cell. 2014 Oct;13(5):817-27. doi: 10.1111/acel.12238. Epub 2014 Jun 17.

 

Methionine restriction restores a younger metabolic phenotype in adult mice with 

alterations in fibroblast growth factor 21.

 

Lees EK(1), Król E, Grant L, Shearer K, Wyse C, Moncur E, Bykowska AS, Mody N,

Gettys TW, Delibegovic M.

 

Author information: 

(1)Institute of Medical Sciences, College of Life Sciences and Medicine,

University of Aberdeen, Aberdeen, AB25 2ZD, UK.

 

Free full text: http://aura.abdn.ac....1/acel12238.pdf

 

Methionine restriction (MR) decreases body weight and adiposity and improves

glucose homeostasis in rodents. Similar to caloric restriction, MR extends

lifespan, but is accompanied by increased food intake and energy expenditure.

Most studies have examined MR in young animals; therefore, the aim of this study 

was to investigate the ability of MR to reverse age-induced obesity and insulin

resistance in adult animals. Male C57BL/6J mice aged 2 and 12 months old were fed

MR (0.172% methionine) or control diet (0.86% methionine) for 8 weeks or 48 h.

Food intake and whole-body physiology were assessed and serum/tissues analyzed

biochemically. Methionine restriction in 12-month-old mice completely reversed

age-induced alterations in body weight, adiposity, physical activity, and glucose

tolerance to the levels measured in healthy 2-month-old control-fed mice. This

was despite a significant increase in food intake in 12-month-old MR-fed mice.

Methionine restriction decreased hepatic lipogenic gene expression and caused a

remodeling of lipid metabolism in white adipose tissue, alongside increased

insulin-induced phosphorylation of the insulin receptor (IR) and Akt in

peripheral tissues. Mice restricted of methionine exhibited increased circulating

and hepatic gene expression levels of FGF21, phosphorylation of eIF2a, and

expression of ATF4, with a concomitant decrease in IRE1α phosphorylation.

Short-term 48-h MR treatment increased hepatic FGF21 expression/secretion and

insulin signaling and improved whole-body glucose homeostasis without affecting

body weight. Our findings suggest that MR feeding can reverse the negative

effects of aging on body mass, adiposity, and insulin resistance through an FGF21

mechanism. These findings implicate MR dietary intervention as a viable therapy

for age-induced metabolic syndrome in adult humans.

 

PMCID: PMC4331744

PMID: 24935677

 

-------

[7] FASEB J. 2015 Jun;29(6):2603-15. doi: 10.1096/fj.14-270348. Epub 2015 Mar 5.

 

UCP1 is an essential mediator of the effects of methionine restriction on energy 

balance but not insulin sensitivity.

 

Wanders D(1), Burk DH(1), Cortez CC(1), Van NT(1), Stone KP(1), Baker M(1),

Mendoza T(1), Mynatt RL(1), Gettys TW(2).

 

Author information: 

(1)*Laboratory of Nutrient Sensing and Adipocyte Signaling, Cell Biology and

Bioimaging Core, and Gene Nutrient Interactions; Pennington Biomedical Research

Center, Baton Rouge, Louisiana, USA. (2)*Laboratory of Nutrient Sensing and

Adipocyte Signaling, Cell Biology and Bioimaging Core, and Gene Nutrient

Interactions; Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA 

gettystw@pbrc.edu.

 

Dietary methionine restriction (MR) by 80% increases energy expenditure (EE),

reduces adiposity, and improves insulin sensitivity. We propose that the

MR-induced increase in EE limits fat deposition by increasing sympathetic nervous

system-dependent remodeling of white adipose tissue and increasing uncoupling

protein 1 (UCP1) expression in both white and brown adipose tissue. In

independent assessments of the role of UCP1 as a mediator of MR's effects on EE

and insulin sensitivity, EE did not differ between wild-type (WT) and Ucp1(-/-)

mice on the control diet, but MR increased EE by 31% and reduced adiposity by 25%

in WT mice. In contrast, MR failed to increase EE or reduce adiposity in

Ucp1(-/-) mice. However, MR was able to increase overall insulin sensitivity by

2.2-fold in both genotypes. Housing temperatures used to minimize (28°C) or

increase (23°C) sympathetic nervous system activity revealed

temperature-independent effects of the diet on EE. Metabolomics analysis showed

that genotypic and dietary effects on white adipose tissue remodeling resulted in

profound increases in fatty acid metabolism within this tissue. These findings

establish that UCP1 is required for the MR-induced increase in EE but not insulin

sensitivity and suggest that diet-induced improvements in insulin sensitivity are

not strictly derived from dietary effects on energy balance.

 

© FASEB.

 

PMCID: PMC4447219 [Available on 2016-06-01]

PMID: 25742717

[Dean Pomerleau]

A Tale of Three Rodents - Part 1: The Grey Squirrel

 

In this and the following two posts, I'm going to further explore some pretty compelling (although circumstantial) evidence in favor of my hypothesis that increasing brown fat, and increasing energy expenditure via UCP-mediated thermogenesis (via cold exposure or other means), improves health & longevity by looking at three long-lived rodents species, the grey squirrel, the naked mole rat, and bats. The latter two are well known to have extended longevity, but not until I started looking into it did I realize the cute little guy in the tree outside my house is a member of a 'longevity superstar' species.

 

I'll start with him, since he's much more analogous to the typical rodents (mice & rats) used in longevity experiments. I'm referring to the Eastern Grey Squirrel (or GS for short) otherwise known by it's scientific name, Sciurus carolinensis.  For those of you who aren't familiar with them, here is what they look like:

 

 

Cute little guys, aren't they?!

 

As I alluded to, GSs are extraordinarily long-lived relative to other terrestrial rodents [Note: I'll deal with flying rodents (bats) and subterranean rodents (nake mole rates) in my next two posts]. Here is a table of lifespans of various common small terrestrial rodents (adapted from [1]):

 

 

As you can see, the GS lives about 6x as long as (non-mutant) mice and rats. For anyone living in the northern latitudes of North America, you know that GSs get a lot of cold exposure. They don't hibernate in winter, but can often be seen like the one above, scurrying around happily in the snow even in the coldest of winter conditions. From [2], "Active grey squirrels have been observed at -30 °C (-22 °F) under a 30 km/h wind." Nevertheless, as you can see from the table, their mean core body temperature is higher (by about 3 °F!) than mice or rats. 

 

So how do they manage to maintain such a high body temperature in cold conditions, and how (probably) do they live so long? You guessed it - via thermogenesis, much of it non-shivering thermogenesis (NST) mediated by BAT. 

 

In [2], researchers kept 65 grey squirrels for several years in individual (2'x2'x4') cages at either warm (25°C = 77°F) or cold (1°C = 34°F!) temperatures. The GSs were fed the following natural diet (which is surprisingly similar to my own diet) :

 

Weekly diet consisted of 300-400 g of shelled nuts (walnuts, filberts, almonds, and peanuts in a 2:2:2:1 mixture) supplemented with an apple and either a carrot, a corncob, or a few mushrooms.

 

Holy cow - take a look at that again. Do you realize how many nuts that is? These GSs were eating about 50g of shelled nuts per day, which is almost 10% of their body weight.  The human equivalent would be to eat about 15 lbs (7 kg) of shelled nuts per day. Ignoring the other food items, the nuts alone provide the squirrels with the human-equivalent of 38,000 kcal/day! I thought I ate a lot :-). 

 

Lets assume the GSs ate 50g of nuts, and got the calorie-equivalent of another 10g of nuts from the other foods in their diet per day. That would be ~60g of nuts / day. At 5.5 kcal/g of nuts that equals 330kcal / day. Since adult GSs weigh about 500g, that would be the equivalent of 660 kcal / kg-BW-per-day.

 

From a human perspective, 660 kcal / kg of body weight per day seems like an awful lot. But how does this compare with other rodents, particular their close-ish (sized) cousin - the rat?  From the post immediately preceding this one, consider this diagram of weight and food intake for laboratory rats. Ignore the meth-restricted rats and focus on the control rats eating a normal, ad-lib diet (open circles): 

 

 

As you can see, the normal fed rats were eating about 15g of food per day. From the Purina rodent chow website, typical lab rat food has 4.09 kcal/g. So that is 61kcal / day. Normalizing for their ~300g average body weight (from left diagram), that means the lab rats were eating ~200 kcal / kg-BW-per-day. 

 

So the caged grey squirrels were naturally eating over 3x as many calories as the ad-lib fed control rats in the meth-restriction study, even after normalizing for body weight. This isn't too surprising given that the GSs were housed at 34°F, and hence had to generate a lot of heat to maintain their body temperature relative to the rats who were housed at a relatively balmy, but still below thermal neutrality, 72°F in the meth-restriction study. In particular, from the full text of [2]:

 

During cold exposure, winter-acclimatized gray squirrels are capable of a peak metabolic rate 13.5 times their predicted standard metabolic rate (SMR). Some 20%-25% of the cold-induced heat production is due to nonshivering thermogenesis (NST). The remainder is attributed to shivering and indicates a capacity to reach a metabolic rate 10 times the predicted SMR by shivering This performance ranks among the highest reported for homeothermic animals. In contrast to shivering, NST is subjected to seasonal variation in the gray squirrel. The maximum noradrenaline-invoked [BAT-mediated] thermogenesis is 3.2-3.5 times greater in cold-acclimatized than in warm-acclimatized animals. 

 

The paradoxical "black" grey squirrel (yup - they come in black too), which are found in more northern regions than the greys, has an even higher capacity for NST than the greys.

 

In short, grey squirrels are champions at cold acclimation and develop large BAT deposits in response to cold exposure. They eat a ton of calories, but stay slim by burning them off through both shivering and non-shivering thermogenesis. And they live an extraordinary long time, 6x as long as their similarly-sized cousins, rats. 

 

While this case study of grey squirrels doesn't prove that eating lots of calories and burning them off via thermogenesis causes increased lifespan, but it is one more piece of very suggestive, circumstantial evidence. In my next posts, we'll look at naked mole rats and bats...

 

--Dean

 

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

[1] Biogerontology. 2015 Aug;16(4):383-97. doi: 10.1007/s10522-015-9571-2. Epub 2015 

Apr 2.

 

Being cool: how body temperature influences ageing and longevity.

 

Keil G(1), Cummings E, de Magalhães JP.

 

Author information: 

(1)Integrative Genomics of Ageing Group, Institute of Integrative Biology,

University of Liverpool, Liverpool, L69 7ZB, UK.

 

Temperature is a basic and essential property of any physical system, including

living systems. Even modest variations in temperature can have profound effects

on organisms, and it has long been thought that as metabolism increases at higher

temperatures so should rates of ageing. Here, we review the literature on how

temperature affects longevity, ageing and life history traits. From poikilotherms

to homeotherms, there is a clear trend for lower temperature being associated

with longer lifespans both in wild populations and in laboratory conditions. Many

life-extending manipulations in rodents, such as caloric restriction, also

decrease core body temperature. Nonetheless, an inverse relationship between

temperature and lifespan can be obscured or reversed, especially when the range

of body temperatures is small as in homeotherms. An example is observed in

humans: women appear to have a slightly higher body temperature and yet live

longer than men. The mechanisms involved in the relationship between temperature 

and longevity also appear to be less direct than once thought with neuroendocrine

processes possibly mediating complex physiological responses to temperature

changes. Lastly, we discuss species differences in longevity in mammals and how

this relates to body temperature and argue that the low temperature of the

long-lived naked mole-rat possibly contributes to its exceptional longevity.

 

PMCID: PMC4486781

PMID: 25832892

 

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

[2] Physiological Zoology 62:1273–1292. (1989)

 

Thermogenic capacity in gray and black morphs of the gray squirrel, Sciurus carolinensis. 

 

Ducharme, M. B., J. Larochelle, and D. Richard.

 

Stable URL: http://www.jstor.org/stable/30156213

Full text: http://sci-hub.io/doi/10.2307/30156213

 

Abstract

 

During cold exposure, winter-acclimatized gray squirrels are capable of a peak metabolic rate 13.5 times their predicted standard metabolic rate (SMR). Some 20%-25% of the cold-induced heat production is due to nonshivering thermogenesis (NST). The remainder is attributed to shivering and indicates a capacity to reach a metabolic rate 10 times the predicted SMR by shivering This performance ranks among the highest reported for homeothermic animals. In contrast to shivering, NST is subjected to seasonal variation in the gray squirrel. The maximum noradrenaline-invoked thermogenesis is 3.2-3.5 times greater in cold-acclimatized than in warm-acclimatized animals. This is primarily interpreted as a means to extend the thermal zone over which muscles can be freely allocated to activities other than shivering While the heat production induced by cold is independent of color morph in warm-acclimatized squirrels, black individuals have a greater NST capacity (by 11%) and a lesser rate of estimated heat loss in the cold (by 18% at -10° C) than gray ones. These results are consistent with the reported predominance of melanistic morphs in the northern part of the species' distribution.

 

 

[Gordo]

Thanks for all the great info Dean.  Its funny to me how so many people talk about CR mimetics when CR itself might just be a BAT mimetic. It seems that many hard core CRONies focus on keeping glucose low and stable.  From what I've been reading about BAT activation, that is one of the major health promoting benefits. Here is one paper related to this:

Brown Adipose Tissue Improves Whole Body Glucose Homeostasis and Insulin Sensitivity in Humans

"These results demonstrate a physiologically significant role of BAT in whole-body energy expenditure, glucose homeostasis, and insulin sensitivity in humans and support the notion that BAT may function as an anti-diabetic tissue in humans."

 

So the "real" scientific studies are out there.  But what's a man to do who wants to apply this to his own life?  I must say, I find the "cool fat burner" guy hilarious (and goofy), but also inspirational.  That guy has done quite a lot of personal experimentation and has created many interesting videos.  His personal experiments are not scientifically rigorous, however many studies published in reputable peer reviewed journals seem to back up the things that he reports.  Anyway, in one of his videos he mentions binging on junkfood including multiple slices of pie plus 18 scoops of ice cream (!) to demonstrate the impact of BAT activation on blood glucose - 1.5 hours after this binge, his blood glucose was only 90, and his fasting number the next morning was 66!  I immediately thought that if this were true, it could become a serious health intervention and may even change the way us "longevists" do things.  

 

So anyway, I have been wanting to try this out on myself to see how my own body reacts.  I have been trying to build my BAT and activate it daily now for a few weeks and I feel like I have made quite a bit of progress in a short amount of time.  Interestingly, I do many if not most of the things from Dean's list of things that activate/build BAT including CR, fasting, low protein (plant based) diet, and I regularly eat almost all of the foods known to activate BAT, so I should be a prime candidate for this stuff.

 

I wasn't going to eat two slices of pie and 18 scoops of ice cream, but as circumstances would have it, I ended up at a "Friendly's" on Sunday with my family (apparently they have not all shut down yet, haha).  I'm not recommending this to anyone else, but I sacrificed myself for science so you guys wouldn't have to, and ate one of their Veggie burgers first, followed by one one of these:

 

• Reese's Pieces Sundae Calories:930
• Fat Calories:480
• Total Fat (g):53
• Saturated Fat (g):26
• Cholesterol (mg):90
• Sodium (mg):360
• Total Carbohydrates (g):95
• Sugars (g):67
•  

The veggie burger stats:

• Total Calories:561
• Fat Calories:244
• Total Fat (g):27
• Saturated Fat (g):6
• Cholesterol (mg):10
• Sodium (mg):834
• Total Carbohydrates (g):66
• Sugars (g):10
• Dietary Fiber (g):5
• Protein (g):13

I went straight home after that and wore the techkewl vest for 3 hours (no exercise) then tested my blood glucose.  It was 76.  The next morning reading was 79.  I would say those readings are pretty good considering the circumstances.  Would have been better to do this with a control first, and take a closer post prandial measurement.  Maybe next time  

I'd be interested in other people's self experimentation results...

 

-Gordo

Edited by Gordo, 15 March 2016 - 09:19 PM.

[Dean Pomerleau]

Great experiment Gordo - thanks for sharing. That looks like a tasty sundae!

 

I'm wondering if you've seen a change in your resting heart rate as a result of cold exposure and BAT activation? Mine seems to have gone up pretty substantially. My Fitbit reports that over the last several months, since I began my cold exposure experiments in earnest, my resting HR has gone from 42-45 BPM to 53-56 BPM. One of the well-known metabolic effects of the elevated norepinephrine that accompanies cold exposure is an elevated heart rate. Have you observed anything similar in your HR?

 

P.S. It's still cold here in Pennsylvania, but I went ahead and ordered a Cool Fat Burner system. I went for the whole 9-yards, getting their $157.99 deluxe combo pack, which ends up being $185 with tax & shipping. I'll report back once I receive and test it.

 

--Dean

[Dean Pomerleau]

A Tale of Three Rodents - Part 2: The Naked Mole Rat

 

In my first post in this three rodent series, I discussed how the hardy, outdoorsy grey squirrel has a lot of BAT (especially in winter), burns a lot of calories via thermogenesis, and lives an extraordinarily long time - 24 years.

 

But what about the rodent longevity champion - the tiny naked mole rat (NMR), scientific name Heterocephalus glaber? They weigh on 35g (a little over an oz, and less than a 1/10th of a rat or squirrel) and live up to a truly remarkable 32 years the longest of any rodent. They aren't nearly as cute as grey squirrels though...

 

 

 

How's that for an understatement?! They've got a face (sort of) that only a mother could love :-). 

 

Also, unlike grey squirrels and almost all other mammals, NMRs are poikilotherms (rather than homeotherms), meaning their body temperature varies considerably with ambient temperature T_a. They spend their entire life underground in quite warm (31°C = 88°F) constant-temperature (daily deviation less than ±1-2°C) burrows in equatorial East Africa. In such constant, balmy conditions, and since they allow their body temperature to vary anyway, you'd think they'd have no trouble with regulating their body temperature and hence not have any need for BAT or thermogenesis - right?

 

But then again - look at them. They're called naked mole rats for a reason - they have no coat to keep them warm like most other mammals do. Plus, their relatively balmy 31°C burrows are still considerably cooler than the 36-38°C body temperature that most rodents maintain.

 

So which is it? Do they or don't they have much BAT and generate much heat through BAT-thermogenesis? If they don't, doesn't that shoot down (or at least cast doubt on) my theory that BAT and BAT-thermogenesis are key for longevity?

 

Reading the abstract, study [1] at first seem pretty damning for my theory. In it, the researchers split 15 NMRs into two groups, one housed at normal burrow temperature (31°C) and the other kept at a temperature that is quite chilly for NMRs (25°C) for over a year. Then they compared the two groups' non-shivering (BAT) thermogenic response to an injection of noradrenaline to simulate cold exposure. Here are the graphs of the results. The cold acclimated NMRs are the hashed bars, and the control NMRs are the open bars:

 

  

 

What's shown is metabolic rate (left) and body temperature (right) of the two groups of NMRs, at baseline (B), after an injection of saline (S), and after an injection of BAT-stimulating noradrenaline (NA). As you can see, the cold-acclimated NMRs had a slightly higher metabolic rate, and slightly higher body temperature, relative to control NMRs either at baseline and after saline injection. While these increases were statistically significant, they were relatively small; nothing to write home about. More to the point, notice that chronic cold exposure does not potentiate the NMRs thermogenic response. If anything, the cold-acclimated NMRs exhibited a slightly smaller increase in metabolic rate and body temperature in response to the NA injection than did controls.

 

So what gives? Why don't NMRs increase their ability to generate heat via BAT-mediated, non-shivering thermogenesis (NST) in response to chronic cold exposure like other rodents, mammals, and people do? The authors suggest that one possible explanation is that evolutionary pressure caused them to lose their ability to cold adapt, in a similar fashion to why/how they lost their hair and (most of) their eyesight:

 

Why does the naked mole-rat not increase its non-shivering thermogenic capacity in response to

chronic cold exposure? From an evolutionary perspective, one might argue that naked mole-rats

have lost the ability to increase the thermogenic capacity of their BAT, for they have exploited a

thermally stable, underground milieu for millennia (Lavocat, 1978). Burrow temperatures, although

relatively high (30–31 °C), are very stable with a [daily] and seasonal temperature range of less than 2

°C. Naked mole-rats, therefore, very rarely encounter temperatures outside their [Thermal Neutral

Zone] (31–34 °C; Buffenstein and Yahav, 1991) and have little need for cold-tolerance.

 

But hold on - does that mean they lack BAT and BAT-thermogenesis? Look at the graph on the left again. The metabolic rate of both groups of NMRs went up by ~350% as a result of the noradrenaline injection. The authors observe that this is a huge increase relative to other rodents:

 

[This] NST response is substantial, being in excess of a 350% increase in VO₂ basal levels.

This is far in excess of that which is seen in laboratory rodents (e.g. Syrian hamster) that

have been acclimated to 5 °C (approx. 200%; Dicker et al., 1995). ... [Similarly] Buffenstein

and Yahav (1991a) [found a] drop in T_a [ambient temperature] of only 2–3 °C below thermoneutrality

resulted in a more than 120% increase in resting metabolism above basal levels [in NMRs].

 

And study [2] shows that NMRs do indeed have BAT that is sensitive to catecholamines like noradrenaline. So here is how the authors of [1] interpret their findings:

 

Relatively speaking then, the cold stress endured by the naked mole-rat at temperatures

even slightly below thermoneutrality is very high and the resulting increase in metabolism is

again indicative of the sustained high thermogenic capacity of their BAT. Because small changes in

T_a below thermoneutrality represent such a severe cold-stress for these mammals, their BAT may

already be maximally stimulated, and as such, thermogenic capacity would be at a maximum

with no further cold-induced increase possible.

 

In other words, due to their nakedness and other factors, naked mole rats are very sensitive to changes in ambient temperature. As a result, the authors suggest that simply by living in their natural habitat they have maxed out the amount of BAT they carry, and their BAT thermogenic capacity, which kicks in to help them generate heat in response to even small changes in ambient temperature. Their BAT is already topped off, so additional chronic cold exposure can't increase it any further. 

 

So in a sense, naked mole rats are the exception that proves the rule. They are the exception because they don't increase BAT levels in response to chronic cold exposure like other rodents and people do. But they "prove the rule" (or more accurately, support my conjecture) that having lots of BAT and employing it to burn calories for heat to maintain body temperature in colder-than-normal conditions is health & longevity promoting. Naked mole rats appear to fit this rule very well, in that they have lots of very sensitive BAT that kicks in for small temperature deviations, and they living a very long time, relative to other rodents.

 

Note: The below is an addendum added a couple days later...

 

As the data from [1] showed, NMRs have an unusually large amount of very sensitive BAT. Study [3] points to a possible explanation. Here is a quote from [3]:

 

"Non-shivering thermogenesis is a major heat production process in mammals that mainly depends on the action of UCP1, one of the 39 vertebrate genes that changed uniquely in NMR [relative to other rodents and humans]...

 

Taken together, these observations indicate a tight association of UCP1 function with the unique thermoregulation in NMR [referencing [1] ]."

 

Interestingly, study [4] found that mutations in the various human UCP genes are also associated with human longevity, and study [5] found that UCP1 gene mutations in humans was specifically associated with variations in individual human longevity. 

 

So there you go, more evidence that naked mole rats have uniquely-tuned, highly-sensitive brown adipose tissue as a result of mutations to their UCP1 gene, and this may at least in part explain their extraordinary longevity. And natural UCP gene mutations in people, including mutations to UCP1, also appear to impact human longevity.

 

Two rodents down, one to go. In my next post - what about bats' BAT?

 

--Dean

 

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

[1] Comp Biochem Physiol A Mol Integr Physiol. 2002 Nov;133(3):827-34.

 

Thermogenic changes with chronic cold exposure in the naked mole-rat

(Heterocephalus glaber).

 

Woodley R(1), Buffenstein R.

 

Author information: 

(1)Department of Anatomical Sciences, Medical School of the University of the

Witwatersrand, 7 York Road, Park Town, 2193, South Africa.

rbuffen@sci..ccny.cuny.edu

 

The naked mole-rat (Heterocephalus glaber) lives communally in a thermally

buffered underground habitat. Here, it relies primarily on ectothermic

(behavioral) mechanisms to maintain body temperature (T(b)). Outside this milieu,

it is unable to effectively regulate T(b) and T(b) tracks that of ambient

temperature (T(a)). Although naked mole-rats, in their natural habitat have

little need for cold-tolerance, we questioned whether or not thermogenic capacity

would change with prolonged (>1 year) exposure to cooler conditions. We

hypothesized that these rodents would not conform to common mammalian patterns

and that non-shivering thermogenic (NST) capacity would be unchanged with chronic

cold exposure. The capacity for NST was assessed following noradrenaline

administration (0.8 mg/kg, s.c.) to lightly anesthetized (pentobarbital 6% m/v 40

mg/kg) animals and monitoring the concomitant changes in oxygen consumption and

T(b). Results concur with the null hypothesis in that prolonged cold exposure did

not elicit any increase in NST capacity (1.52+/-0.17 ml O(2)/g/h,

cold-acclimated; 1.73+/-0.31 ml O(2)/g/h, control; P>0.05). Rapid heat loss

across their uninsulated integument may necessitate continuous maximal

stimulation of brown adipose tissue (BAT), and as such, prevent any further

increase in thermogenic capacity following cold exposure.

 

PMID: 12443938

 

----------

[2] J Anat. 1997 Apr;190 ( Pt 3):321-6.

Catecholaminergic innervation of interscapular brown adipose tissue in the naked
mole-rat (Heterocephalus glaber).

Daly TJ(1), Williams LA, Buffenstein R.

Author information:
(1)Department of Anatomical Sciences, University of the Witwatersrand,
Johannesburg, South Africa.

The thermogenic potential of the interscapular brown fat pad in the naked
mole-rat Heterocephalus glaber, that exhibits poikilothermic thermal responses to
changing temperatures is reported. Histological and ultrastructural study of the
brown fat pad showed that it consists of layers of skeletal muscle interposed
between the layers of brown adipose tissue with both unilocular and multilocular
adipocytes. Large numbers of mitochondria were present between and around the
lipid droplets of these cells. Glyoxylic acid condensation, used to demonstrate
catecholaminergic nerves, was evident in low concentrations in the connective
tissue between the brown adipocytes. A 3-dimensional computer-aided
reconstruction of the fat pad showed the extent and ramification of nerves and
blood vessels between the adipocytes. These findings show that although the naked
mole-rat is regarded as an endothermic poikilotherm, it possesses anatomical
features usually found in homeothermic mammals, which are essential for
thermogenesis.

PMCID: PMC1467613
PMID: 9147219

 

-----------

[3] Nature. 2011 Oct 12;479(7372):223-7. doi: 10.1038/nature10533.

 

Genome sequencing reveals insights into physiology and longevity of the naked

mole rat.

 

Kim EB(1), Fang X, Fushan AA, Huang Z, Lobanov AV, Han L, Marino SM, Sun X,

Turanov AA, Yang P, Yim SH, Zhao X, Kasaikina MV, Stoletzki N, Peng C, Polak P,

Xiong Z, Kiezun A, Zhu Y, Chen Y, Kryukov GV, Zhang Q, Peshkin L, Yang L, Bronson

RT, Buffenstein R, Wang B, Han C, Li Q, Chen L, Zhao W, Sunyaev SR, Park TJ,

Zhang G, Wang J, Gladyshev VN.

 

Author information: 

(1)Department of Bioinspired Science, Ewha Womans University, Seoul, 120-750,

Korea.

 

Free full text: http://www.ncbi.nlm....les/PMC3319411/

 

The naked mole rat (Heterocephalus glaber) is a strictly subterranean,

extraordinarily long-lived eusocial mammal. Although it is the size of a mouse,

its maximum lifespan exceeds 30 years, making this animal the longest-living

rodent. Naked mole rats show negligible senescence, no age-related increase in

mortality, and high fecundity until death. In addition to delayed ageing, they

are resistant to both spontaneous cancer and experimentally induced

tumorigenesis. Naked mole rats pose a challenge to the theories that link ageing,

cancer and redox homeostasis. Although characterized by significant oxidative

stress, the naked mole rat proteome does not show age-related susceptibility to

oxidative damage or increased ubiquitination. Naked mole rats naturally reside in

large colonies with a single breeding female, the 'queen', who suppresses the

sexual maturity of her subordinates. They also live in full darkness, at low

oxygen and high carbon dioxide concentrations, and are unable to sustain

thermogenesis nor feel certain types of pain. Here we report the sequencing and

analysis of the naked mole rat genome, which reveals unique genome features and

molecular adaptations consistent with cancer resistance, poikilothermy,

hairlessness and insensitivity to low oxygen, and altered visual function,

circadian rythms and taste sensing. This information provides insights into the

naked mole rat's exceptional longevity and ability to live in hostile conditions,

in the dark and at low oxygen. The extreme traits of the naked mole rat, together

with the reported genome and transcriptome information, offer opportunities for

understanding ageing and advancing other areas of biological and biomedical

research.

 

PMCID: PMC3319411

PMID: 21993625

 

--------

[4] 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, hearth 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.

 

PMCID: PMC3246500

PMID: 22216339

 

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

[5]  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.

 

PMID: 21827845

[Gordo]

Hey Dean, yes, my resting heart rate is higher than before.  I'll have to analyze my data to compare to pre-cold exposure readings.  I am one of those people that for a long time thought a super low heart rate and metabolism were critical for longevity, but I have since changed my mind about this based on the observational science.  There is no evidence that your heart for example "wears out" faster just because its had more "lifetime beats" compared to someone else.  And a higher  metabolism doesn't necessarily mean your body's cells are dividing faster, therefore resulting in shorter telomeres/accumulation of genetic damage, etc.  Maybe that is the general "rule" but BAT burning up excess calories seems to be one exception to the rule.  Although I'd love to see some more data confirming that.

 

FYI:  When I was looking at the cool fat burner product page, at least the one I was looking at said it came with 1 kg of phase change material.  The techkewl vest comes with 2.2 kg of PCM, so more than double.  Just wanted to point that out.  That said, I would like to design my own vest that better targets BAT, which I plan to do at some point.  Lastly, I got the techkewl in "like new" condition from amazon warehouse for $85, and it looked brand new to me, so anyone interested in a little savings should check for that...

Edited by Gordo, 02 March 2016 - 05:00 PM.

[Dean Pomerleau]

Over on the methionine restriction thread, Sirtuin posed some questions regarding cold exposure. I'm answering them here since this seems like the appropriate thread for such a discussion. So here goes.

 

What are your thoughts on cold exposure and cardiovascular / health risks?

 

Cold Exposure Promotes Atherosclerotic Plaque Growth:

http://www.cell.com/...4131(13)00247-7

 

A quick search on the title of that paper (PMID 23823482) would have shown Al Pater posed the same question, pointing to the same study, in this post. I addressed it in this post and again in this one. Bottom line - that study uses a very poor rodent model of atherosclerosis. A much better mouse model of CVD shows dramatic benefits of cold exposure, as do human studies. Here is a brand new review article [1] of both the animal and human research on brown fat and CVD, which concludes:

 

Through these mechanisms, BAT activation reduces plasma triglyceride and cholesterol levels and attenuates diet-induced atherosclerosis development.

 

Low temperature was associated with greater risk of mortality from cardiovascular disease: http://www.ncbi.nlm....les/PMC3857249/

 

At temperatures below 20 °C (68 °F), increased risk of death has been observed, and winter deaths reportedly rise at a rate of about 1.4% per degree below 18 °C (64 °F): http://news.bbc.co.u...lth/5372296.stm

 

Yes - that isn't too surprising. Low temperatures put greater stress on the cardiovascular systems of people at risk for CVD. In fact, my dad died at age 69 shoveling snow. He was 60 lbs overweight, diabetic and had high blood pressure. He'd smoked 2 packs a day for 20 years, before quitting after a heart attack at age 55. 

 

Your second link suggests something similar, referring to the 

 

Most of them [deaths in winter] are due to strokes and heart attacks.

 

But correlation is not causation. Just because more people die of heart attacks and strokes in wintertime doesn't mean that cold exposure promotes the development of CVD. It appears just the opposite, as described above.

 

Cold climate is a risk factor for thyroid cancer:

http://www.ncbi.nlm....pubmed/25558467

 

That's a funny one [2]. From the free full text, here is their scatter plot of thyroid cancer rate as a function of temperature for each of the 50 states:

 

 

First off, that doesn't look like a very strong correlation to me. Second, there are a lot of things that people living in warm southern states do that I could imagine influencing the risk of thyroid cancer, that have nothing to do with ambient temperature.

 

Finally, and most importantly, look at the Y-scale of the graph. Change in risk is going from 5 to 10 cases of thyroid cancer per 100,000 people. Thyroid cancer is in fact quite rare. Last year, just under 2000 people died in the US of thyroid cancer, according to the American Cancer Society. This compares with the over 600,000 people who die from cardiovascular disease in the US each year. Here is a graphic for comparison of those two risks.

 

Thyroid cancer deaths: █ █ 

 

Cardiovascular deaths: █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ 

 

                                 █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ 

 

                                 █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ 

 

                                 █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ 

 

                                 █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ 

 

                                 █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ 

 

                                 █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ 

 

                                 █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ 

 

                                 █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ 

 

                                 █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ 

 

                                 █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ 

 

                                 █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ █ 

 

 

So even if cold exposure did modestly increase thyroid cancer risk (which is questionable), it seems a small price to pay for decreased risk of our number one killer, cardiovascular disease.

 

In the summer, I appear much more vascular with warm hands, warm feet, a large network of thick arteries at the surface of my skin, etc.  Yet, in the winter, I get cold hands, cold feet, cold ears, a cold nose, and my vascularity recedes (I otherwise find the cold quite comfortable, haha.)  It's very difficult to draw blood for me in a cold lab.  It seems like circulation is directly impaired here, and that this would not be an ideal stressor?  I've tried various methods to acclimate to the cold and prevent these effects from occuring, but it's fairly automatic for me at a low level unless I dramatically increase calories + protein and aerobic activity to increase thermogenesis (eg. my cold shower post exercise.)

 

I wear gloves when exposing myself to cold to keep my hands from getting too cold. I have a pair with the fingertips cut off so I can type ☺

 

Regarding calories - if you read over this entire thread, perhaps you'll become a lot less convinced that restricting calories per se is particularly beneficial...

 

--Dean

 

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

[1] Circ Res. 2016 Jan 8;118(1):173-82. doi: 10.1161/CIRCRESAHA.115.306647.

 

Role of Brown Fat in Lipoprotein Metabolism and Atherosclerosis.

 

Hoeke G(1), Kooijman S(1), Boon MR(1), Rensen PC(1), Berbée JF(1).

 

Author information: 

(1)From the Department of Medicine, Division of Endocrinology and Einthoven

Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 

Leiden, The Netherlands.

 

Atherosclerosis, for which hyperlipidemia is a major risk factor, is the leading 

cause of morbidity and mortality in Western society, and new therapeutic

strategies are highly warranted. Brown adipose tissue (BAT) is metabolically

active in human adults. Although positron emission tomography-computed tomography

using a glucose tracer is the golden standard to visualize and quantify the

volume and activity of BAT, it has become clear that activated BAT combusts fatty

acids rather than glucose. Here, we review the role of brown and beige adipocytes

in lipoprotein metabolism and atherosclerosis, with evidence derived from both

animal and human studies. On the basis of mainly data from animal models, we

propose a model in which activated brown adipocytes use their intracellular

triglyceride stores to generate fatty acids for combustion. BAT rapidly

replenishes these stores by internalizing primarily lipoprotein

triglyceride-derived fatty acids, generated by lipoprotein lipase-mediated

hydrolysis of triglycerides, rather than by holoparticle uptake. As a

consequence, BAT activation leads to the generation of lipoprotein remnants that 

are subsequently cleared via the liver provided that an intact apoE-low-density

lipoprotein receptor pathway is present. Through these mechanisms, BAT activation

reduces plasma triglyceride and cholesterol levels and attenuates diet-induced

atherosclerosis development. Initial studies suggest that BAT activation in

humans may also reduce triglyceride and cholesterol levels, but potential

antiatherogenic effects should be assessed in future studies.

 

© 2016 American Heart Association, Inc.

 

PMID: 26837747

 

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

[2] Clin Thyroidol. 2014 Oct;26(10):273-276.

 

Cold Climate Is a Risk Factor for Thyroid Cancer.

 

Lehrer S, Rosenzweig KE.

 

Free full text: http://www.ncbi.nlm....les/PMC4280500/

 

BACKGROUND: The incidence rates of differentiated thyroid cancers of all sizes

increased between 1988 and 2005 in both men and women. Exposure to ionizing

radiation is the best-established environmental risk factor for thyroid cancer.

Nonionizing radiation from cell phones has also been implicated. A positive

correlation between all-cancer incidence rates and latitude and an inverse

correlation between all-cancer incidence rates and temperature have been

reported. In the present study, we examined the relationship between thyroid

cancer incidence and average temperature in 50 U.S. states.

METHODS: The age-adjusted incidence of thyroid cancer is from U.S. Cancer

Statistics Working Group, United States Cancer Statistics: 1999-2010, Incidence

and Mortality Web-based Report (Atlanta: Department of Health and Human Services,

Centers for Disease Control and Prevention and National Cancer Institute; 2013,

available at: www.cdc.gov/uscs). Average temperature by state is from the

National Climatic Data Center, National Oceanic and Atmospheric Administration

(http://www.ncdc.noaa.gov). Information on high-impact exposure to nuclear

radiation by state is from the National Radiation Exposure Screening and

Education Program, U.S. Health Resources and Services Administration

(http://www.hrsa.gov/...diationexposure). Cell-phone

subscriber data for 2007 is from the Governing State and Local Sourcebook

(http://sourcebook.governing.com). Mean elevation and latitude of U.S. states is 

from "Elevations and Distances in the United States," Reston, VA: U.S. Geological

Survey, April 29, 2005 (http://pubs.er.usgs.gov).

RESULTS: There was a significant negative correlation between average temperature

by state and the age-adjusted incidence of all thyroid cancers (r(2) = -0.212, P 

= 0.001). Because of the possible effects of ionizing radiation exposure from

nuclear testing and nonionizing radiation exposure from cell phones, multiple

linear regression analysis was performed. The analysis was done only for all

thyroid cancers and for thyroid cancers in whites. The data from blacks and

Hispanics were too fragmentary to analyze. In all thyroid cancers and thyroid

cancers in whites, there was a significant negative correlation between average

temperature and incidence that was unrelated to nuclear testing, cell-phone use, 

altitude, and latitude and was independent of the significant correlation of

cell-phone subscriptions per population with thyroid cancer in whites.

CONCLUSIONS: Living in a cold-climate state, such as Alaska, doubles the risk of 

thyroid cancer as compared with a warm state such as Texas. Because of climate

change, a significantly raised risk of heat-related and cold-related mortality is

expected in the years to come. The elderly will be most at risk. No doubt,

incidence patterns of thyroid cancer and other cancers may be affected.

 

PMCID: PMC4280500

PMID: 25558467

[Dean Pomerleau]

Gordo,

 

Thanks for the confirming that you've seen an increase in your resting heart rate as well as result of cold exposure. 

 

FYI:  When I was looking at the cool fat burner product page, at least the one I was looking at said it came with 1 kg of phase change material.  The techkewl vest comes with 2.2 kg of PCM, so more than double.  Just wanted to point that out. 

 

The Cool Fat Burner combo pack I bought is listed as weighing 3kg. Plus I plan to experiment with creating my own phase change cooling packs, as we discussed here. By the way, have you tried making your own cooling packs?

 

--Dean

[Dean Pomerleau]

Before my bat BAT post, just a quick addition to my naked mole rat (NMR) and BAT thermogenesis post (I've also edited the post above, but nobody following along in 'real time' would see it).

 

As the data from PMID 12443938 showed, NMRs have an unusually large amount of very sensitive BAT. Study [1] points to a possible cause. It found that:

 

"Non-shivering thermogenesis is a major heat production process in mammals that mainly depends on the action of UCP1, one of the 39 vertebrate genes that changed uniquely in NMR [relative to other rodents and humans]...

 

Taken together, these observations indicate a tight association of UCP1 function with the unique thermoregulation in NMR [referencing PMID 12443938 that I discussed above]."

 

Interestingly, study [2] found that mutations in the various human UCP genes are also associated with human longevity, and study [3] found that mutations to the UCP1 gene in humans was specifically associated with variations in individual human longevity. 

 

So there you go, more evidence that naked mole rats have uniquely-tuned, highly-sensitive brown adipose tissue as a result of mutations to their UCP1 gene, and this may explain at least part of their extraordinary longevity. And natural UCP gene mutations in people, including mutations to UCP1, also appear to impact human longevity.

 

--Dean

 

-----------

[1] Nature. 2011 Oct 12;479(7372):223-7. doi: 10.1038/nature10533.

 

Genome sequencing reveals insights into physiology and longevity of the naked

mole rat.

 

Kim EB(1), Fang X, Fushan AA, Huang Z, Lobanov AV, Han L, Marino SM, Sun X,

Turanov AA, Yang P, Yim SH, Zhao X, Kasaikina MV, Stoletzki N, Peng C, Polak P,

Xiong Z, Kiezun A, Zhu Y, Chen Y, Kryukov GV, Zhang Q, Peshkin L, Yang L, Bronson

RT, Buffenstein R, Wang B, Han C, Li Q, Chen L, Zhao W, Sunyaev SR, Park TJ,

Zhang G, Wang J, Gladyshev VN.

 

Author information: 

(1)Department of Bioinspired Science, Ewha Womans University, Seoul, 120-750,

Korea.

 

Free full text: http://www.ncbi.nlm....les/PMC3319411/

 

The naked mole rat (Heterocephalus glaber) is a strictly subterranean,

extraordinarily long-lived eusocial mammal. Although it is the size of a mouse,

its maximum lifespan exceeds 30 years, making this animal the longest-living

rodent. Naked mole rats show negligible senescence, no age-related increase in

mortality, and high fecundity until death. In addition to delayed ageing, they

are resistant to both spontaneous cancer and experimentally induced

tumorigenesis. Naked mole rats pose a challenge to the theories that link ageing,

cancer and redox homeostasis. Although characterized by significant oxidative

stress, the naked mole rat proteome does not show age-related susceptibility to

oxidative damage or increased ubiquitination. Naked mole rats naturally reside in

large colonies with a single breeding female, the 'queen', who suppresses the

sexual maturity of her subordinates. They also live in full darkness, at low

oxygen and high carbon dioxide concentrations, and are unable to sustain

thermogenesis nor feel certain types of pain. Here we report the sequencing and

analysis of the naked mole rat genome, which reveals unique genome features and

molecular adaptations consistent with cancer resistance, poikilothermy,

hairlessness and insensitivity to low oxygen, and altered visual function,

circadian rythms and taste sensing. This information provides insights into the

naked mole rat's exceptional longevity and ability to live in hostile conditions,

in the dark and at low oxygen. The extreme traits of the naked mole rat, together

with the reported genome and transcriptome information, offer opportunities for

understanding ageing and advancing other areas of biological and biomedical

research.

 

PMCID: PMC3319411

PMID: 21993625

 

--------

[2] 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, hearth 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.

 

PMCID: PMC3246500

PMID: 22216339

 

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[3]  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.

 

PMID: 21827845