Cold Exposure & Other Mild Stressors for Increased Health & Longevity

[Dean Pomerleau]

[Admin Note: This is a series of posts originally on another thread that started on the topic of how cold exposure can have beneficial effects for health and longevity despite increasing calorie expenditure. I debated where to move them, since they seem to fit General Health & Longevity, CR Practice, and CR Science. I finally opted for CR Science, since you'll see if you haven't been reading them already, they bear directly on CR and CR mimetics.  If anyone feels strongly this was the wrong choice, I'll be happy to move the thread to another forum.  --Dean]

 

 

Rodney,

 

Whenever I see someone use the word "surely", I figure the writer isn't very sure about, or doesn't have real evidence to support, what they are about to say. I'm guilty of it sometimes myself.

 

People's appetites differ for a lot of reasons, many of them without negative health implications. Genetics is one example that can alter metabolic rate and therefore hunger (remember the ob/ob mice who ate more but didn't live shorter lives).

 

Exercise or exposure to cold (and extra brown fat that cold exposure can create/promote) will increase calorie expenditure without detrimental effects. In fact, perhaps my favorite study of all time (except for the suffering of the animals involved) was the famous "rats with cold feet" study [1] by John Holloszy. Holloszy found that rats who lived their lives standing in a cold puddle of water ate 44% more than normally-housed rats, but nonetheless stayed thin and didn't live any shorter lives than the normally-housed rats. In fact they lived slightly longer and got less cancer.

 

Our friend Josh Mitteldorf did a whole blog post about the hormetic benefits of cold exposure, and how it casts serious doubt (if not debunks) the popular "rate of living" theory of aging.

 

--Dean (who composed this post while pedalling shirtless and wearing just bike shorts on his stationary bike in his 59 degF basement to maximize hormesis...   )

 

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[1] J Appl Physiol (1985). 1986 Nov;61(5):1656-60.

Longevity of cold-exposed rats: a reevaluation of the "rate-of-living theory".

Holloszy JO, Smith EK.

It has been postulated that increased energy expenditure results in shortened
survival. To test this "rate-of-living theory" we examined the effect of raising
energy expenditure by means of cold exposure on the longevity of rats. Male
6-mo-old SPF Long-Evans rats were gradually accustomed to immersion in cool water
(23 degrees C). After 3 mo they were standing in the cool water for 4 h/day, 5
days/wk. They were maintained on this program until age 32 mo. The cold exposure
resulted in a 44% increase in food intake (P less than 0.001). Despite their
greater food intake, the cold-exposed rats' body weights were significantly lower
than those of control animals from age 11 to 32 mo. The average age at death of
the cold-exposed rats was 968 +/- 141 days compared with 923 +/- 159 days for the
controls. The cold exposure appeared to protect against neoplasia, particularly
sarcomas; only 24% of the necropsied cold-exposed rats had malignancies compared
with 57% for the controls. The results of this study provide no support for the
concept that increased energy expenditure decreases longevity.

PMID: 3781978 [PubMed - indexed for MEDLINE]

[AlPater]

Translating animal model research: does it matter that our rodents are cold?

Maloney SK, Fuller A, Mitchell D, Gordon C, Overton JM.

Physiology (Bethesda). 2014 Nov;29(6):413-20. doi: 10.1152/physiol.00029.2014. Review.

PMID: 25362635 Free Article

http://physiologyonline.physiology.org/content/29/6/413.long

http://physiologyonline.physiology.org/content/29/6/413.full-text.pdf+html

 

Abstract

 

Does it matter that rodents used as preclinical models of human biology are routinely housed below their thermoneutral zone? We compile evidence showing that such rodents are cold-stressed, hypermetabolic, hypertensive, sleep-deprived, obesity-resistant, fever-resistant, aging-resistant, and tumor-prone compared with mice housed at thermoneutrality. The same genotype of mouse has a very different phenotype and response to physiological or pharmacological intervention when raised below or at thermoneutrality.

 

"Rodent Longevity

 

The rodent models that have attracted public attention, perhaps more than any others, are those demonstrating artificially enhanced longevity. Engineering a mouse's hypothalamus to overproduce uncoupling protein 2 results in the local production of heat in the hypothalamus. Because the hypothalamus is the most thermosensitive region in the mammalian body and provides the majority of the input signal for thermoregulation (26), the local heating results in a lower than normal Tb everywhere else in the body. Those engineered mice also live longer than normal (14), providing evidence of an association between Tb, energetics, and longevity (3).

 

There are other mouse genotypes that live longer than average. These genotypes produce dwarf strains, and their LCTs are higher than those of the average mouse. They tend to have lower Tb than normal mice, even at Ta of 26°C (7). The hypopituitary Ames and Snell strains live for ~1,150 days compared with 720 days for a normal mouse (8). In dwarf mice, the longevity appears to be related to increased metabolic rate (3). The long-lived growth hormone-resistant (GHR-KO) strain has a metabolic rate higher than that of wild-type mice when housed at 23°C but not when housed at 30°C (3), implying that enhanced longevity would not be evident in the TNZ. That implication is manifested in the C57Black-6 (B6) strain of mouse that lives for ~785 days (35) when its lifespan is extended by calorie restriction (CR). Placing B6 mice onto a CR diet, where they receive 60% of their normal daily energy requirement, extends their life to ~1,148 days at 21°C (35). If the B6 mice are fed a CR diet at thermoneutrality, they live for ~810 days, not significantly different from the 785 days of the control-fed mice (35). So CR does not extend lifespan in B6 mice in their TNZ. Koizumi (35) thought that the explanation lay in the restricted use of torpor at the higher Ta, but Bartke (3) reports that the long-lived genotypes do not use torpor and thus maintain a high metabolism when they are exposed to 21°C. There is clearly much we do not understand about the interactions between Ta, Tb, metabolism, and longevity."

[Dean Pomerleau]

Al,

 

The paper you just posted above (PMID: 25362635) is a goldmine of interesting information relevant to the benefits of cold exposure! Thanks so much for sharing it. 

 

The paragraph you posted is exactly the one that is most relevant. The authors present evidence that cold exposure is not only helpful in its own right, independent of CR, but also necessary for the benefits of CR to manifest, at least in some, commonly studied strains of rodents:

 

Placing B6 mice onto a CR diet, where they receive 60% of their normal daily energy requirement, extends their life to ~1,148 days at 21°C [72 DegF] (35). If the B6 mice are fed a CR diet at thermoneutrality [86 DegF], they live for ~810 days, not significantly different from the 785 days of the control-fed mice (35). So CR does not extend lifespan in B6 mice in their TNZ [thermal neutral zone].

 

And perhaps as importantly, that cold exposure doesn't produce benefits as a result of inducing a hibernation-like state of torpor and reduced metabolic rate, as previously thought (by Roy Walford and others, citation (35)) but quite the opposite. The benefit results from (or at least occur in the presence of) an increased metabolic rate exhibited by skinny CR mice housed in relatively cool conditions in order to maintain their body temperature:

 

Koizumi (35) thought that the explanation lay in the restricted use of torpor at the higher Ta [ambient temperature - i.e. Walford, Koizumi et al thought rodents didn't go into hibernation-like state as a result of CR if housed in warm conditions and so didn't live longer], but Bartke (3) reports that the long-lived genotypes do not use torpor and thus maintain a high metabolism when they are exposed to 21°C. 

 

and:

In dwarf mice, the longevity appears to be related to increased metabolic rate (3). The long-lived growth hormone-resistant (GHR-KO) strain has a metabolic rate higher than that of wild-type mice when housed at 23°C but not when housed at 30°C (3), implying that enhanced longevity would not be evident in the TNZ.

 

This accords with the "rats with cold feet" study (pmid 3781978) I discussed above, where rats ate 44% more calories and burned them to stay warm while standing in cold water. As a result they had a higher metabolic rate, stayed thin and lived just as long as rats that were kept warm and ate 44% fewer calories.

 

I strongly suspect calories burned to stay warm are burned more "cleanly" than calories burned to support normal metabolic processes, and hence aren't (as) detrimental to health / longevity.

 

Way back in the heyday of the CR email list, I spent several months trying to wrap my head around the likely mechanism for this "free lunch" for calories burned to stay warm. I've always suspected, and still suspect, it has to do with uncoupling proteins - which open up channels to allow protons to leak through the mitochondrial membrane, which generates heat in the process, but does not contribute to the production of the cell's energy storage/transport molecule ATP (hence the name 'uncoupling proteins' since they uncouple proton movement across the mitochondrial membrane from the normal process of ATP generation).

 

If my memory serves me correctly (Michael or Brian could correct me if I'm wrong), letting protons leak across the mitochondrial membrane reduces the proton gradient between the inside and outside of the mitochondrial membrane, making the oxidative phosphorylation process of ATP generation less likely to "fumble" electrons, which results in a cascade of effects leading to free radical production and damage to the mitochondria, which eventually contributes to cellular and organism aging. Or so the theory goes...

 

It was all extremely complicated, and recent reviews of the role of uncoupling proteins in aging and longevity [1][2], seem to support the idea that they are indeed important, but exactly how and why is still somewhat of a mystery.

 

But there is ample evidence (e.g. [3] and [4]) that cold exposure increases uncoupling protein expression. But the benefits of cold exposure could (also) result from an entirely different mechanism, like hormesis-induced upregulation of beneficial heat shock proteins, or simply enabling one to stay thin, thereby reducing lifetime obesity burden and so live longer.

 

But regardless of how cold exposure works, whether it is through less damage, better repair, or some other mechanism entirely, it appears that it may indeed increase lifespan relative to thermal neutral conditions, even in (especially in?) CRed mammals.

 

Makes me feel less resentful of living in a place where the high temperature tomorrow is going to be 14 degF (-10C). No problem getting exposed to cold here!

 

Stay thin, stay cold, live long and prosper.

 

--Dean

 

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[1] Curr Aging Sci. 2010 Jul;3(2):102-12.

 

Uncoupling protein-2 and the potential link between metabolism and longevity.

 

Andrews ZB(1).

 

Author information: 

(1)Department of Physiology, Monash University, Clayton, VIC 3183 Australia.

zane.andrews@med.monash.edu.au

 

The discovery of novel uncoupling proteins (UCP2 and UCP3) over 10 years ago

heralded a new era of research in mitochondrial uncoupling in a diverse range of 

tissues. Despite the research vigor, debate stills surrounds the exact function

of these uncoupling proteins. For example, the level of uncoupling, the mechanism

and mode of action are all under-appreciated at this point in time. Our recent

work has used genetic mouse models to focus on the physiological relevance of

UCP2. We have used these mouse models to better appreciate the role UCP2 in human

health and disease. In this review we focus on new research showing that UCP2

promotes longevity by shifting a given cell towards fatty acid fuel utilization. 

This metabolic hypothesis underlying UCP2-dependent longevity suggests that UCP2 

is critically positioned to maintain fatty acid oxidation and restrict subsequent

oxidative damage allowing sustained mitochondrial oxidative capacity and

mitochondrial biogenesis. These mechanisms converge within the cell to boost cell

function and metabolism and the net result promotes healthy aging and increased

lifespan. Finally, UCP2 is a useful dietary and therapeutic target to promote

lifespan and is an important mitochondrial protein connecting longevity to

metabolism.

 

PMID: 20158496

 

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[2] Pflugers Arch. 2010 Jan;459(2):269-75. doi: 10.1007/s00424-009-0729-0. Epub 2009 

Sep 17.

 

The role of mitochondrial uncoupling proteins in lifespan.

 

Dietrich MO(1), Horvath TL.

 

Author information: 

(1)Section of Comparative Medicine, Yale University School of Medicine, New

Haven, CT 06520, USA.

 

The increased longevity in modern societies raised the attention to biological

interventions that could promote a healthy aging. Mitochondria are main

organelles involved in the production of adenosine triphosphate (ATP), the

energetic substrate for cellular biochemical reactions. The production of ATP

occurs through the oxidative phosphorylation of intermediate substrates derived

from the breakdown of lipids, sugars, and proteins. This process is coupled to

production of oxygen reactive species (ROS) that in excess will have a

deleterious role in cellular function. The damage promoted by ROS has been

emphasized as one of the main processes involved in senescence. In the last

decades, the discovery of specialized proteins in the mitochondrial inner

membrane that promote the uncoupling of proton flux (named uncoupling

proteins-UCPs) from the ATP synthase shed light on possible mechanisms implicated

in the buffering of ROS and consequently in the process of aging. UCPs are

responsible for a physiological uncoupling that leads to decrease in ROS

production inside the mitochondria. Thus, induction of uncoupling through UCPs

could decrease the cellular damage that occurs during aging due to excess of ROS.

This review will focus on the evidence supporting these mechanisms.

 

PMCID: PMC2809791

PMID: 19760284

 

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[3] 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

 

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[4] Int J Biochem Cell Biol. 1998 Jan;30(1):7-11.

 

The uncoupling protein, thermogenin.

 

Palou A(1), Picó C, Bonet ML, Oliver P.

 

Author information: 

(1)Departament de Biologia Fonamental i Ciêncies de la Salut, Universitat de les 

Illes Balears, Palma de Mallorca 07071, Spain.

 

The uncoupling protein (UCP) or thermogenin is a 33 kDa inner-membrane

mitochondrial protein exclusive to brown adipocytes in mammals that functions as 

a proton transporter, allowing the dissipation as heat of the proton gradient

generated by the respiratory chain and thereby uncoupling oxidative

phosphorylation. Thermogenesis (heat production) in brown adipose tissue, which

is activated in response to cold exposure or chronic overeating, depends largely 

on UCP activity. Norepinephrine, released from sympathetic terminals and acting

via beta-adrenoceptors and cAMP, is the main positive regulator of both UCP

synthesis and activity. Brown fat thermogenesis plays a critical role in

thermoregulation and in overall energy balance, at least in rodents. Manipulation

of thermogenesis, whether through UCP or through analogous uncoupling proteins,

could be an effective strategy against obesity.

 

PMID: 9597749

[martin knight]

Placing B6 mice onto a CR diet, where they receive 60% of their normal daily energy requirement, extends their life to ~1,148 days at 21°C [72 DegF] (35). If the B6 mice are fed a CR diet at thermoneutrality [86 DegF], they live for ~810 days, not significantly different from the 785 days of the control-fed mice (35). So CR does not extend lifespan in B6 mice in their TNZ [thermal neutral zone].

 

But are mice in the TNZ in CR at all as they are no longer spending so much energy heating their bodies? Is there an experiment that compared raising mice in TNZ and below TNZ that calibrated intake so the two groups weighed the same? This would be better for our purposes as it would - for a given bodyweight - compare the decision to eat more to combat cold to eating less but staying warm.

[Dean Pomerleau]

Martin wrote:

But are mice in the TNZ [thermal neutral zone - i.e. warm conditions] in CR at all as they are no longer spending so much energy heating their bodies? Is there an experiment that compared raising mice in TNZ and below TNZ that calibrated intake so the two groups weighed the same? This would be better for our purposes as it would - for a given bodyweight - compare the decision to eat more to combat cold to eating less but staying warm.

 

Very good question Martin. Fortunately, the very study we are discussing did just the thing you were asking for - i.e. feed the CR mice raised in the warm environment (86F) less than CR mice raised in the cool environment (72F) so as to match their weight, and therefore their net calorie restriction. Here is the section on the diets from the full text of reference [35] in the above post:

 

The mice were randomly assigned to a control (Ct/B6)

group, an energy-restricted (ER/B6) group, both maintained at room temperature

or to an energy-restricted group maintained at 30°C (ERI/B6). 

 

The Ct/B6 mice received 27 g (407 kJ) of the control diet per week, which averaged 20% less than

the amount consumed by B6 female mice given free access to the diet. The ER/B6

mice received 17 g (235 kJ) of the ER diet per week and the ERI/B6 mice 13 g

(175 kJ) of the ERI diet. 

 

[The] ER and ERI mice consumed about the same amounts of protein, fat, vitamins and

minerals but less carbohydrate than the corresponding controls. 

 

So the control mice housed as cool temperatures received 27g of food, the cool-housed CR mice received 17g (40% less than controls), and the warm-housed CR mice received 13g of food, ~20% less than the cool-housed CR mice to account for the fewer calories they needed to burn to keep warm.

 

Here is a graph of the body weight of the three groups of mice over their lifespan:

As you can see, the control mice gained a lot of weight over their lifespan, at their peak weighing twice as much as the two CR groups. But the calorie titration between the two CR groups was effective at matching body weight, despite different caloric needs (and intake) to compensate for the difference in calories spent for thermal regulation.

 

And here are the survival curves:

 

 

These results are striking. The mice housed at thermal neutrality (ERI/B6), eating less than half the calories and weighing half as much as the control mice housed in cool conditions (Ct/B6), had a median survival time that was statistically indistinguishable from the control mice - 810 vs. 778 days. To their credit, the maximum lifespan of the warm-house CR mice was extended relative to the controls, as you can see.

 

In contrast, the CR mice housed at a cool temperature (ER/B6), also weighed half as much as controls, and who ate 20% more calories than the weight-matched warm-housed CR mice, had a median lifespan 40% longer than either the cool-housed controls or the warm-housed CR mice (1143 days). They ended the study when the last of the warm-house CR mice died, at which point 8 of the cool-housed CR mice were still alive, so the maximum lifespan for the cool-housed CR mice was pretty much guaranteed to be extended relative to the warm-housed CR mice.

 

The authors interpreted these results to imply that torpor was required for CR benefits. But as the review discussed above (PMID: 25362635) suggests, long-lived mice don't exhibit torpor when exposed to the temperature used in this study, but instead maintain a higher metabolic rate to stay warm, as implied by the 20% extra calories the cool-housed CR mice required to maintain the same weight as the warm-housed CR mice in this study.

 

But again, whatever the mechanism, this study seems to show that for this commonly-studied strain of mice, housing them at what is for them a thermally neutral temperature erases all the longevity benefit of CR (at least for the average animal), even when their food is restricted enough to keep them very thin relative to cool-housed controls. Or put another way, CR and cold exposure was required to extend the median lifespan of these animals - CR without cold exposure didn't cut it.

 

--Dean

 

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[35] Mech Ageing Dev. 1996 Nov 29;92(1):67-82.

A tumor preventive effect of dietary restriction is antagonized by a high housing
temperature through deprivation of torpor.

Koizumi A(1), Wada Y, Tuskada M, Kayo T, Naruse M, Horiuchi K, Mogi T, Yoshioka
M, Sasaki M, Miyamaura Y, Abe T, Ohtomo K, Walford RL.

full text: http://www.sciencedirect.com.sci-hub.io/science/article/pii/S0047637496018039

Energy restriction (ER) has proven to be the only effective means of retarding
aging in mice. The mechanisms of multiplicity of effects of ER on aging remain,
however, fragmentary. ER induces daily torpor, the induction of which is reduced
by increasing the ambient temperature to 30 degrees C. The effects of preventing
hypothermia in ER animals were studied in terms of the expected consequences of
ER on survival, disease pattern and a number of physiological parameters in
autoimmune prone MRL/lpr mice and lymphoma prone C57BL, 6 mice. The results
demonstrate that torpor plays a crucial role in the prevention of lymphoma
development but does not have an affect on other aspects of ER, such as
prevention of autoimmune diseases.

PMID: 9032756

[martin knight]

Thanks Dean, that is a remarkable result and quite counter-intuitive. I will make one quibble: the longest lived 1/3 or so of the ERI (warm housed) mice - those who presumably adapted well to the diet - did live longer (about 1100 days) than the equivalent 1/3 of the controls (900) if not the ER (cooler housed but fed more) mice (1250).

 

BTW I'm getting a site in Russian when I click on links to papers so am hesitant to proceed further :)

[Dean Pomerleau]

I agree Martin. Quite a surprising result, but not inconsistent with the overall picture that there is definitely something more than "calories, calories, calories" going on with CR.

 

I will make one quibble: the longest lived 1/3 or so of the ERI (warm housed) mice - those who presumably adapted well to the diet - did live longer (about 1100 days) than the equivalent 1/3 of the controls (900) if not the ER (cooler housed but fed more) mice (1250).

 

No need to quibble, I acknowledged the same thing in my synopsis of the study when I said "To their credit, the maximum lifespan of the warm-house CR mice was extended relative to the controls". But notice that at around 900 days, only those 1/3rd well-adapted and therefore longest-lived warm-housed CR mice are still alive, while at that same time point about 3/4 of cool-housed CR mice are still alive. Do you really want to bet that you'll be one of the lucky few whose CR response kicks in when living in thermally neutral conditions?

 

Looked at another way, the data from PMID 9032756 can be interpreted as follows:

 

CRed mice housed at what for them is an uncomfortably cool temperature ate 20% more, weighted the same, and lived 40% longer on average than CRed mice housed at a comfortably temperature.

 

So much for "calories, calories, calories". And contrary to my recent contentions, this data suggests CR involves more than just obesity avoidance, since the warm mice avoided obesity but didn't live any longer on average than the controls. One could speculate that cold stress on top of an energy deficit is required to kick the metabolism into CR mode, at least in these mice.

 

As you suggested, a pretty startling result.

 

BTW I'm getting a site in Russian when I click on links to papers so am hesitant to proceed further :)

 

Yes - that is sci-hub.io. Its probably asking you to input a captcha to prove you're a human before it will show you the full text of the paper.

 

--Dean

[martin knight]

From what I remember of the discussions on the email list over longevity benefits of exercise vs CR there wasn't much of a conclusion but the rodent evidence tended toward exercise not helping for a given bodyweight (i.e. increased intake to counter the extra expenditure) and even for no compensating increase in intake leading to decreased weight. Why body heat production - which is akin to exercise it seems to me - would be different is a mystery. 

[Dean Pomerleau]

Martin,

Why body heat production - which is akin to exercise it seems to me - would be different is a mystery. 

 

While I'm a big proponent of exercise, burning calories in exercise is far from equivalent to the way the body expends calories to regulate temperature, affording plenty of opportunities for the impact of the two activities on health and longevity to diverge.  Yes, exercise (and other voluntary physical activities) does generate heat and can help maintain body temperature, but it is just one of many ways of accomplishing that end, as illustrated in this amusing graphic:

 

 

 

Uncoupling proteins, either UCP1 in brown adipose tissue (aka BAT or 'brown fat'), or UCP3 in muscle tissue (to a lesser extent - see below), are a major mechanism by which the body generates heat for thermoregulation. Proton leakage across the mitochondrial membrane, mostly controlled by these UCPs, accounts for 20-30% of the resting metabolic rate in rats [2] - so they have a big effect!

 

And an increase in this way of expending energy has been found to reduce reactive oxygen species (ROS) generation in and around the mitochondria, which could be one way to explain how cold exposure, which raises uncoupling protein levels, benefits health and longevity. Here is a graphic (from [2]) of the many ways that upregulating UCPs can benefit health:

 

 

 

It was once thought that adult humans had little brown fat, and therefore little UCP1, and that there was nothing that could be done to change that. But recently it was discovered that not only do we have BAT, but the level of brown fat in the human body can be increased via cold exposure. You've just gotta love the name of this study - it's called the "Impact of Chronic Cold Exposure in Humans (ICEMAN)" study [1]. In it, researchers found that having men sleep in a cool room (66F) for a month increased brown fat levels and activity by 42% relative to thermal neutral sleeping, as well as improved insulin sensitivity and glucose metabolism. In contrast, sleeping in a warm (81F) room decreased the level of brown fat and its metabolic activity by about 20% in the men.

 

So like in rodents, it appears brown fat and UCP1 can be increased in humans via cold exposure, which is likely to be a good thing based on the rodent longevity data discussed in previous posts, not to mention the finding from [1] of improved insulin sensitivity.

 

But what about UCP3, which we have much more of than UCP1 and which is the homolog of UCP1 but which occurs in skeletal muscles rather than (or in addition to) brown fat? What does UCP3 do and what influences UCP3 expression?

 

Unlike UCP1, it is not clear that UCP3 contributes significantly to thermal regulation [6], despite the fact that it can indeed uncouple the ATP synthesis process in mitochondria just like UCP1, and hence contribute to heat generation. Its true role doesn't appear to be very clear, according to review article [2], but it definitely seems to reduce ROS generation in the mitochondria of skeletal muscles, and thereby protect mitochondria from oxidative damage, which is a very good thing. Other known or suspected benefits of UCP3 upregulation are shown in the diagram above.

 

So what can be done to upregulate UCP3 levels in muscles? 

 

Cold exposure appears to only modestly (if at all [5]) and perhaps only temporarily increase the level of UPC3 in muscles [4], more as a result of increased energy expenditure than via a direct increase in expression of mRNA for UCP3, which strangely was actually downregulated by cold. What appears to be happening is that cold exposure [4], exercise [5], fasting [6], and particularly the combination, i.e. exercising in the fasting state [3], increases the level of free fatty acids in muscle cells (FFAs are used by muscles as fuel when glucose isn't available), and it is these FFAs that facilitate the expression of of UCP3 mRNA, and subsequently increase UCP3 levels in muscle cells.

 

TL;DR - Cold exposure, fasting, exercise, and especially exercise in the fasted state can upregulate the two major uncoupling proteins, UCP1 and UCP3. These proteins appear to enable the body to burn calories more "cleanly", reducing oxidative damage and increasing insulin sensitivity. Upregulation of these proteins are likely just one of several pathways by which cold exposure, fasting and exercise have beneficial effects on health and longevity.

 

--Dean

 

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[1] Diabetes. 2014 Nov;63(11):3686-98. doi: 10.2337/db14-0513. Epub 2014 Jun 22.

 

Temperature-acclimated brown adipose tissue modulates insulin sensitivity in

humans.

 

Lee P(1), Smith S(1), Linderman J(1), Courville AB(2), Brychta RJ(1), Dieckmann

W(3), Werner CD(1), Chen KY(1), Celi FS(4).

 

Free full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4207391/

 

In rodents, brown adipose tissue (BAT) regulates cold- and diet-induced

thermogenesis (CIT; DIT). Whether BAT recruitment is reversible and how it

impacts on energy metabolism have not been investigated in humans. We examined

the effects of temperature acclimation on BAT, energy balance, and substrate

metabolism in a prospective crossover study of 4-month duration, consisting of

four consecutive blocks of 1-month overnight temperature acclimation (24 °C

[month 1] → 19 °C [month 2] → 24 °C [month 3] → 27 °C [month 4]) of five healthy 

men in a temperature-controlled research facility. Sequential monthly acclimation

modulated BAT reversibly, boosting and suppressing its abundance and activity in 

mild cold and warm conditions (P < 0.05), respectively, independent of seasonal

fluctuations (P < 0.01). BAT acclimation did not alter CIT but was accompanied by

DIT (P < 0.05) and postprandial insulin sensitivity enhancement (P < 0.05),

evident only after cold acclimation. Circulating and adipose tissue, but not

skeletal muscle, expression levels of leptin and adiponectin displayed reciprocal

changes concordant with cold-acclimated insulin sensitization. These results

suggest regulatory links between BAT thermal plasticity and glucose metabolism in

humans, opening avenues to harnessing BAT for metabolic benefits.

 

© 2014 by the American Diabetes Association. Readers may use this article as long

as the work is properly cited, the use is educational and not for profit, and the

work is not altered.

 

PMCID: PMC4207391

PMID: 24954193

 

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[2] Front Physiol. 2015 Feb 10;6:36. doi: 10.3389/fphys.2015.00036. eCollection 2015.

 

Mitochondrial uncoupling proteins and energy metabolism.

 

Busiello RA(1), Savarese S(2), Lombardi A(3).

 

Author information: 

(1)Dipartimento di Scienze e Tecnologie, Università degli Studi del Sannio

Benevento, Italy. (2)Dipartimento di Scienze e Tecnologie Ambientali, Biologiche 

e Farmaceutiche, Seconda Università degli Studi di Napoli Caserta, Italy.

(3)Dipartimento di Biologia, Università degli Studi di Napoli Napoli, Italy.

 

Understanding the metabolic factors that contribute to energy metabolism (EM) is 

critical for the development of new treatments for obesity and related diseases. 

Mitochondrial oxidative phosphorylation is not perfectly coupled to ATP

synthesis, and the process of proton-leak plays a crucial role. Proton-leak

accounts for a significant part of the resting metabolic rate (RMR) and therefore

enhancement of this process represents a potential target for obesity treatment. 

Since their discovery, uncoupling proteins have stimulated great interest due to 

their involvement in mitochondrial-inducible proton-leak. Despite the widely

accepted uncoupling/thermogenic effect of uncoupling protein one (UCP1), which

was the first in this family to be discovered, the reactions catalyzed by its

homolog UCP3 and the physiological role remain under debate. This review provides

an overview of the role played by UCP1 and UCP3 in mitochondrial

uncoupling/functionality as well as EM and suggests that they are a potential

therapeutic target for treating obesity and its related diseases such as type II 

diabetes mellitus.

 

PMCID: PMC4322621

PMID: 25713540

 

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

[3] Am J Physiol Endocrinol Metab. 2002 Jan;282(1):E11-7.

 

Effect of acute exercise on uncoupling protein 3 is a fat metabolism-mediated

effect.

 

Schrauwen P(1), Hesselink MK, Vaartjes I, Kornips E, Saris WH, Giacobino JP,

Russell A.

 

Author information: 

(1)Department of Human Biology, Maastricht University, 6200 MD Maastricht, The

Netherlands. p.schrauwen@hb.unimaas.nl

 

Human and rodent uncoupling protein (UCP)3 mRNA is upregulated after acute

exercise. Moreover, exercise increases plasma levels of free fatty acid (FFA),

which are also known to upregulate UCP3. We investigated whether the upregulation

of UCP3 after exercise is an effect of exercise per se or an effect of FFA levels

or substrate oxidation. Seven healthy untrained men [age: 22.7 +/- 0.6 yr; body

mass index: 23.8 +/- 1.0 kg/m(2); maximal O2 uptake (VO2 max): 3,852 +/- 211

ml/min] exercised at 50% VO2 max for 2 h and then rested for 4 h. Muscle biopsies

and blood samples were taken before and immediately after 2 h of exercise and 1

and 4 h in the postexercise period. To modulate plasma FFA levels and fat/glucose

oxidation, the experiment was performed two times, one time with glucose

ingestion and one time while fasting. UCP3 mRNA and UCP3 protein were determined 

by RT-competitive PCR and Western blot. In the fasted state, plasma FFA levels

significantly increased (P < 0.0001) during exercise (293 +/- 25 vs. 1,050 +/-

127 micromol/l), whereas they were unchanged after glucose ingestion (335 +/- 54 

vs. 392 +/- 74 micromol/l). Also, fat oxidation was higher after fasting (P <

0.05), whereas glucose oxidation was higher after glucose ingestion (P < 0.05).

In the fasted state, UCP3L mRNA expression was increased significantly (P < 0.05)

4 h after exercise (4.6 +/- 1.2 vs. 9.6 +/- 3.3 amol/microg RNA). This increase

in UCP3L mRNA expression was prevented by glucose ingestion. Acute exercise had

no effect on UCP3 protein levels. In conclusion, we found that acute exercise had

no direct effect on UCP3 mRNA expression. Abolishing the commonly observed

increase in plasma FFA levels and/or fatty acid oxidation during and after

exercise prevents the upregulation of UCP3 after acute exercise. Therefore, the

previously observed increase in UCP3 expression appears to be an effect of

prolonged elevation of plasma FFA levels and/or increased fatty acid oxidation.

 

PMID: 11739077

 

---------

[4] International Journal of Obesity (2002) 26, 450-457. DOI: 10.1038/sj/ijo/0801943

 

The effect of mild cold exposure on UCP3 mRNA expression and UCP3 protein content in humans

 

Abstract

 

OBJECTIVE: In rodents, adaptive thermogenesis in response to cold exposure and high-fat feeding is accomplished by the activation of the brown adipose tissue specific mitochondrial uncoupling protein, UCP1. The recently discovered human uncoupling protein 3 is a possible candidate for adaptive thermogenesis in humans. In the present study we examined the effect of mild cold exposure on the mRNA and protein expression of UCP3.

 

SUBJECTS: Ten healthy male volunteers (age 24.4±1.6 y; height 1.83±0.02 m; weight 77.3±3.0 kg; percentage body fat 19±2)

 

DESIGN: Subjects stayed twice in the respiration chamber for 60 h (20.00-8.00 h); once at 22°C (72°F), and once at 16°C (61°F). After leaving the respiration chamber, muscle biopsies were taken and RT-competitive-PCR and Western blotting was used to measure UCP3 mRNA and protein expression respectively.

 

RESULTS: Twenty-four-hour energy expenditure was significantly increased at 16°C compared to 22°C (P<0.05). At 16°C, UCP3T (4.6±1.0 vs 7.7±1.5 amol/µg RNA, P=0.07), UCP3L (2.0±0.5 vs 3.5±0.9 amol/µg RNA, P=0.1) and UCP3S (2.6±0.6 vs 4.2±0.7 amol/µg RNA, P=0.07) mRNA expression tended to be lower compared with at 22°C, whereas UCP3 protein content was, on average, not different. However, the individual differences in UCP3 protein content (16-22°C) correlated positively with the differences in 24 h energy expenditure (r=0.86, P<0.05).

 

CONCLUSION: The present study suggests that UCP3 protein content is related to energy metabolism in humans and might help in the metabolic adaptation to cold exposure. However, the down-regulation of UCP3 mRNA with mild cold exposure suggests that prolonged cold exposure will lead to lower UCP3 protein content. What the function of such down-regulation of UCP3 could be is presently unknown.

 

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

[5]  Int J Sports Med. 2012 Feb;33(2):94-100. doi: 10.1055/s-0031-1287799. Epub 2011

Nov 23.

 

Human mRNA response to exercise and temperature.

 

Slivka DR(1), Dumke CL, Tucker TJ, Cuddy JS, Ruby B.

 

Author information: 

(1)University of Nebraska at Omaha, HPER, Omaha 68182, USA. dslivka@unomaha.edu

 

The purpose of this research was to determine the mRNA response to exercise in

different environmental temperatures. 9 recreationally active males (27±1 years, 

77.4±2.7  kg, 13.5±1.5% fat, 4.49±0.15  L · min (-1) VO2 max) completed 3 trials 

consisting of 1 h cycling exercise at 60% Wmax followed by a 3 h recovery in the 

cold (7°C), room temperature (20°C), and hot (33°C) environments. Muscle biopsies

were obtained pre, post, and 3 h post exercise for the analysis of glycogen and

mRNA. Expired gases were collected to calculate substrate use. PGC-1α increased

to a greater degree in the cold trial than in the room temperature trial

(p=0.036) and the hot trial (p=0.006). PGC1-α mRNA was also higher after the room

temperature trial than the hot trial (p=0.050). UCP3 and MFN2 mRNA increased with

exercise (p<0.05), but were unaffected by temperature. COX was unaffected by

exercise or temperature. Muscle glycogen decreased with exercise (p<0.05), but

was no different among trials. Whole body VO2 was lower during exercise in the

cold than exercise in the heat. However, VO2 was higher during recovery in the

cold trial than in the room temperature and hot trials (p<0.05). This study

presents evidence of PGC-1α temperature sensitivity in human skeletal muscle.

 

© Georg Thieme Verlag KG Stuttgart · New York.

 

PMID: 22113536

 

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

[6] J Appl Physiol (1985). 2006 Jul;101(1):12-3.

 

Tough love: left out in the cold, but not abandoned, by UCP3.

 

Cline GW.

 

Free full text: http://jap.physiology.org/content/101/1/12

 

Comment on

    J Appl Physiol (1985). 2006 Jul;101(1):339-47.

 

PMID: 16782833

[Dean Pomerleau]

All,

 

In my last post, I said the uncoupling proteins UCP1 and UCP3 are likely to be just one of several pathways that cold exposure, fasting and exercise might increase health and longevity.

 

Here is another, very interesting one.

 

Recently it has been shown [1] that  transgenic mice that overexpress fibroblast growth factor 21 (FGF21), a hormone produced in the liver, share many characteristics with long-lived dwarf mice, including small size, enhanced insulin sensitivity and a blunted GH/IGF-1 signaling axis. But more importantly, these transgenic mice lived 40% longer than normal mice without the FGF21 mutation [1]. Importantly, there were no differences in food intake, physical activity, oxygen consumption or respiratory exchange ratio between the mutant and normal mice. In fact, if anything the FGF21 mutant mice ate a bit more than the normal mice once adjustments were made for their smaller body size.  Here are the survival curves for the mutant FGF21 transgenic mice (Tg) vs. wild-type (WT) controls:

 

 

In fascinating gene expression analysis, the authors of [1] confirmed that that FGF21 concentration is increased as a result of 24h of fasting in normal mice, a result which was previously well known. But what was really interesting was that continuous calorie restriction did not upregulate FGF21 gene expression. But they found that the FGF21 protein and calorie restriction both influenced other genes in a similar fashion. In other words, FGF21 appears to serve as a master gene/hormone that acts as a CR mimetic. The authors of [1] conclude:

 

These data suggest that FGF21 may extend lifespan by regulating a small subset of genes also regulated by caloric restriction in [the] liver.

 

So if FGF21 is a CR mimetic, how might we upregulate it with having to wait for gene therepy?

 

Well as we just observed, short-term fasting is one way to do it, and may be part of the mechanism by which intermittent fasting has beneficial effects. So Mattson may be right, and Michael, not so much...

 

But in addition, cold exposure (66F vs controls at 75F for 12h) apparently upregulates FGF21 expression in people by 37%, and this increase in FGF21 predicted increase in 24h energy expenditure [2].

 

Finally, exercise has also been shown to increase the level of FGF21 in humans [3][4]. In fact, two weeks of treadmill exercise increased FGF21 levels by 66% in healthy young women tested in [3].

 

So here again we see that three mild stressors, intermittent fasting, cold exposure and exercise, can increase the level of a master hormone (FGF21), the overexpression of which has proven to dramatically increase health and longevity in rodents. 

 

--Dean

 

--------

[1] Elife. 2012 Oct 15;1:e00065. doi: 10.7554/eLife.00065.

 

The starvation hormone, fibroblast growth factor-21, extends lifespan in mice.

 

Zhang Y(1), Xie Y, Berglund ED, Coate KC, He TT, Katafuchi T, Xiao G, Potthoff

MJ, Wei W, Wan Y, Yu RT, Evans RM, Kliewer SA, Mangelsdorf DJ.

 

Free full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3466591/

 

Fibroblast growth factor-21 (FGF21) is a hormone secreted by the liver during

fasting that elicits diverse aspects of the adaptive starvation response. Among

its effects, FGF21 induces hepatic fatty acid oxidation and ketogenesis,

increases insulin sensitivity, blocks somatic growth and causes bone loss. Here

we show that transgenic overexpression of FGF21 markedly extends lifespan in mice

without reducing food intake or affecting markers of NAD+ metabolism or AMP

kinase and mTOR signaling. Transcriptomic analysis suggests that FGF21 acts

primarily by blunting the growth hormone/insulin-like growth factor-1 signaling

pathway in liver. These findings raise the possibility that FGF21 can be used to 

extend lifespan in other species.DOI:http://dx.doi.org/10.7554/eLife.00065.001.

 

PMCID: PMC3466591

PMID: 23066506

 

-----------

[2] J Clin Endocrinol Metab. 2013 Jan;98(1):E98-102. doi: 10.1210/jc.2012-3107. Epub 

2012 Nov 12.

 

Mild cold exposure modulates fibroblast growth factor 21 (FGF21) diurnal rhythm

in humans: relationship between FGF21 levels, lipolysis, and cold-induced

thermogenesis.

 

Lee P(1), Brychta RJ, Linderman J, Smith S, Chen KY, Celi FS.

 

Author information: 

(1)Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes

and Digestive and Kidney Diseases, National Institutes of Health, Building 10,

Clinical Research Center, 10 Center Drive, Bethesda, Maryland 20892, USA.

pcylee@gmail.com

 

CONTEXT: Cold exposure stimulates fibroblast growth factor 21 (FGF21) secretion

in animals, enhancing the cold-induced thermogenesis (CIT) response through

browning of white adipose tissue. In humans, the effects of cold exposure on

circulating FGF21 levels are unknown.

OBJECTIVE: Our objective was to evaluate the effects of mild cold exposure on

circulating FGF21 and its relationship with CIT and lipolysis in humans.

DESIGN AND SETTING: We conducted a randomized, single-blind, crossover

intervention study at the National Institutes of Health Clinical Center.

PARTICIPANTS: Participants were healthy adults.

INTERVENTION: Subjects were exposed to a 12-h exposure to 24 or 19 C in a

whole-room indirect calorimeter.

OUTCOME MEASURES: Energy expenditure, plasma FGF 21, nonesterified fatty acid,

and adipose tissue microdialysis glycerol concentrations were evaluated.

RESULTS: At 24 C, plasma FGF21 exhibited a diurnal rhythm, peaking at 0800 h [110

(59-178) pg/ml], and progressively dropped to a nadir at 1700 h [41 (21-71)

pg/ml, P < 0.0001] before rising at 1900 h [60 (11-81) pg/ml, P < 0.0001].

Exposure at 19 C lessened the diurnal reduction of FGF21 observed at 24 C from

0800-1700 h and augmented overall FGF21 levels by 37 ± 45% (P = 0.01). The change

in area under the curve plasma FGF21 between 19 and 24 C correlated positively

with the change in area under the curve adipose microdialysate glycerol (R(2) =

0.35, P = 0.04) but not with nonesterified fatty acid. Cold-induced increase in

FGF21 predicted greater rise in energy expenditure during cold exposure (β =

0.66, P = 0.027), independent of age, gender, fat mass, and lean mass.

CONCLUSIONS: Mild cold exposure increased circulating FGF21 levels, predicting

greater lipolysis and CIT. A small reduction in environmental temperature is

sufficient to modulate FGF21 diurnal rhythm in humans, which may mediate

cold-induced metabolic changes similar to those in animals.

 

PMCID: PMC3537100

PMID: 23150685

 

----------

[3] PLoS One. 2012;7(5):e38022. doi: 10.1371/journal.pone.0038022. Epub 2012 May 31.

 

Exercise increases serum fibroblast growth factor 21 (FGF21) levels.

 

Cuevas-Ramos D(1), Almeda-Valdés P, Meza-Arana CE, Brito-Córdova G, Gómez-Pérez

FJ, Mehta R, Oseguera-Moguel J, Aguilar-Salinas CA.

 

Free full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3365112/

 

BACKGROUND: Fibroblast growth factor 21 (FGF21) increases glucose uptake. It is

unknown if FGF21 serum levels are affected by exercise.

METHODOLOGY/PRINCIPAL FINDINGS: This was a comparative longitudinal study.

Anthropometric and biochemical evaluation were carried out before and after a

bout of exercise and repeated after two weeks of daily supervised exercise. The

study sample was composed of 60 sedentary young healthy women. The mean age was

24±3.7 years old, and the mean BMI was 21.4±7.0 kg/m². The anthropometric

characteristics did not change after two weeks of exercise. FGF21 levels

significantly increased after two weeks of exercise (276.8 ng/l (142.8-568.6) vs.

(460.8 (298.2-742.1), p<0.0001)). The delta (final-basal) log of serum FGF21,

adjusted for BMI, showed a significant positive correlation with basal glucose

(r = 0.23, p = 0.04), mean maximal heart rate (MHR) (r = 0.54, p<0.0001), mean

METs (r = 0.40, p = 0.002), delta plasma epinephrine (r = 0.53, p<0.0001) and

delta plasma FFAs (r = 0.35, p = 0.006). A stepwise linear regression model

showed that glucose, MHR, METs, FFAs, and epinephrine, were factors independently

associated with the increment in FGF21 after the exercise program (F = 4.32;

r² = 0.64, p<0.0001).

CONCLUSIONS: Serum FGF21 levels significantly increased after two weeks of

physical activity. This increment correlated positively with clinical parameters 

related to the adrenergic and lipolytic response to exercise.

TRIAL REGISTRATION: ClinicalTrials.gov NCT01512368.

 

PMCID: PMC3365112

PMID: 22701542  [PubMed - indexed for MEDLINE]

 

--------

[4] PLoS One. 2013 May 7;8(5):e63517. doi: 10.1371/journal.pone.0063517. Print 2013.

 

Acute exercise induces FGF21 expression in mice and in healthy humans.

 

Kim KH(1), Kim SH, Min YK, Yang HM, Lee JB, Lee MS.

 

Author information: 

(1)Department of Medicine, Samsung Medical Center, Sungkyunkwan University School

of Medicine, 50 Irwon-dong Gangnam-gu, Seoul, Korea.

 

Fibroblast growth factor 21 (FGF21) plays an important role in the regulation of 

energy homeostasis during starvation and has an excellent therapeutic potential

for the treatment of type 2 diabetes in rodents and monkeys. Acute exercise

affects glucose and lipid metabolism by increasing glucose uptake and lipolysis. 

However, it is not known whether acute exercise affects FGF21 expression. Here,

we showed that serum FGF21 level is increased in mice after a single bout of

acute exercise, and that this is accompanied by increased serum levels of free

fatty acid, glycerol and ketone body. FGF21 gene expression was induced in the

liver but not in skeletal muscle and white adipose tissue of mice after acute

exercise, and further, the gene expression levels of hepatic peroxisome

proliferator-activated receptor α (PPARα) and activating transcription factor 4

(ATF4) were also increased. In addition, we observed increased FGF21 level in

serum of healthy male volunteers performing a treadmill run at 50 or 80% VO2max. 

These results suggest that FGF21 may also be associated with exercise-induced

lipolysis in addition to increased catecholamines and reduced insulin.

 

PMCID: PMC3646740

PMID: 23667629

[Dean Pomerleau]

Here is an easy to read popular press article on brown fat and the efforts of researchers to increase it in humans to help with weight loss. Two passages I found most interesting:

 

None of us actually possesses very much brown fat. It’s estimated that healthy adults typically have only 50 to 60 grams of it, located mostly in the neck around the collar bones. Small amounts of it can also be found along the spine. This can burn at least 200 kilocalories a day – which doesn’t seem like a lot. That’s the caloric equivalent of about four Timbits. But over time, that’s sufficient enough to have a profound effect on a person’s body weight.

 

and:

His research shows this same effect [converting muscle stem cells to brown fat cells] occurs by simply exposing mice to cold. “They shiver, and the muscle stem cells turn into brown fat,” he says.

 

“Of course, all of us would be quite thin if it weren’t for central heating,” he adds.

 

The fact we can maximize the calorie-burning power of brown fat simply by being chilly certainly sounds alluring. Unfortunately, ramping up our brown fat through cold exposure isn’t ideal.

 

“People don’t really want to sit around in their underwear in their house at 5 or 10 degrees Celsius because it’s uncomfortable,” Steinberg says, adding that cold exposure also prompts people to eat more, which would likely offset any benefits.

 

It seems to me the researcher underestimates the lengths to which some of us will go. 

 

Speaking of shivering mice and brown fat. I'm still struck by the fact that virtually all CR rodent experiments have been conducted at room temperature, which for rats and mice is cool and therefore a thermal stressor, increasing levels of brown fat and causing them to burn calories to maintain their body temperature.  There is evidence to suggest that without this type of cold stress, CR doesn't extend lifespan, at least for the average rodent...

 

--Dean

[AlPater]

http://www.dailymail.co.uk/health/article-3400205/Have-scientists-discovered-elixir-youth-Hormone-extends-lifespan-40-protecting-immune-against-ravages-age.html

 

Have scientists discovered the elixir of youth? Hormone 'extends lifespan by 40%, protecting the immune system against the ravages of age' 

 

FGF21 is produced by the thymus gland and extends lifespan by 40%

Scientists discovered it protects the immune system from effects of age

Hope it could help treat elderly, obesity, cancer and type 2 diabetes 

By LIZZIE PARRY FOR DAILYMAIL.COM

PUBLISHED: 22:32 GMT, 14 January 2016

 

It is the Holy Grail of health research, discovering the key to help people live longer.

 

Now scientists believe they may be one step closer.

 

A team at Yale School of Medicine have identified a hormone, produced by the thymus glad, extends lifespan by 40 per cent.

 

Their findings reveal increased levels of the hormone, known as FGF21, protects the immune system against the ravages of age. 

 

Researchers said the study could have implications in the future for improving immune function in the elderly, for obesity, and for diseases such as cancer and type 2 diabetes.

 

When it is functioning normally, the thymus produces new T cells for the immune system.

 

But with age, the gland becomes fatty and loses its ability to produce the vital cells.

 

This loss of new T cells in the body is one cause of increased risk of infections and certain cancers in the elderly.

 

Researchers led by Vishwa Deep Dixit, professor of comparative medicine and immunobiology at Yale, studied transgenic mice with elevated levels of FGF21.

 

They blocked the gene's function, before studying the impact of decreasing levels of FGF21 on the immune system.

 

Their results showed that increasing the level of FGF21 in old mice protected the thymus from age-related fatty degeneration and increased the ability of the thymus to produce new T cells.

 

Meanwhile, FGF21 deficiency accelerated the degeneration of the thymus in old mice.

 

Professor Dixit said: 'We found that FGF21 levels in thymic epithelial cells is several fold higher than in the liver, therefore FGF21 acts within the thymus to promote T cell production.

 

'Elevating the levels of FGF21 in the elderly or in cancer patients who undergo bone marrow transplantation may be an additional strategy to increase T cell production, and thus bolster immune function.' 

 

The hormone, produced by the thymus glad, extends lifespan by 40 per cent. Their findings reveal increased levels of the hormone, known as FGF21, protects the immune system against the ravages of age

 

Professor Dixit added that FGF21 is produced in the liver as an endocrine hormone.

 

Its levels increase when calories are restricted to allow fats to be burned when glucose levels are low.

 

FGF21 is a metabolic hormone that improves insulin sensitivity and also induces weight loss.

 

Therefore it is being studied for its therapeutic effects in type 2 diabetes and obesity. 

 

Professor Dixit said future studies will focus on understanding how FGF21 protects the thymus from aging, and whether elevating FGF21 through the use of drugs, could extend human lifespan and lower the incidence of disease caused by age-related loss of immune function. 

 

He added: 'We will also look to developing a way to mimic calorie restriction to enhance immune function without actually reducing calorie intake.' 

 

The study was published in the Proceedings of the National Academy of Sciences.

 

Cynthia Kenyon: Experimenting for longer lives (related)

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Prolongevity hormone FGF21 protects against immune senescence by delaying age-related thymic involution.

Youm YH, Horvath TL, Mangelsdorf DJ, Kliewer SA, Dixit VD.

Proc Natl Acad Sci U S A. 2016 Jan 11. pii: 201514511. [Epub ahead of print]

PMID: 26755598

http://www.pnas.org.sci-hub.io/content/early/2016/01/06/1514511113.short

 

Abstract

 

Age-related thymic degeneration is associated with loss of naïve T cells, restriction of peripheral T-cell diversity, and reduced healthspan due to lower immune competence. The mechanistic basis of age-related thymic demise is unclear, but prior evidence suggests that caloric restriction (CR) can slow thymic aging by maintaining thymic epithelial cell integrity and reducing the generation of intrathymic lipid. Here we show that the prolongevity ketogenic hormone fibroblast growth factor 21 (FGF21), a member of the endocrine FGF subfamily, is expressed in thymic stromal cells along with FGF receptors and its obligate coreceptor, βKlotho. We found that FGF21 expression in thymus declines with age and is induced by CR. Genetic gain of FGF21 function in mice protects against age-related thymic involution with an increase in earliest thymocyte progenitors and cortical thymic epithelial cells. Importantly, FGF21 overexpression reduced intrathymic lipid, increased perithymic brown adipose tissue, and elevated thymic T-cell export and naïve T-cell frequencies in old mice. Conversely, loss of FGF21 function in middle-aged mice accelerated thymic aging, increased lethality, and delayed T-cell reconstitution postirradiation and hematopoietic stem cell transplantation (HSCT). Collectively, FGF21 integrates metabolic and immune systems to prevent thymic injury and may aid in the reestablishment of a diverse T-cell repertoire in cancer patients following HSCT.

 

KEYWORDS:

 

FGF21; aging; inflammation; metabolism; thymus

[Sthira]

10 g for $70 on http://www.amazon.com/gp/aw/d/B010GG0KZW/ref=mp_s_a_1_2?qid=1453257934&sr=8-2&pi=SY200_QL40&keywords=FGF21&dpPl=1&dpID=51vexQ-cGfL&ref=plSrch

[Dean Pomerleau]

10 g for $70 on http://www.amazon.com/gp/aw/d/B010GG0KZW/ref=mp_s_a_1_2?qid=1453257934&sr=8-2&pi=SY200_QL40&keywords=FGF21&dpPl=1&dpID=51vexQ-cGfL&ref=plSrch

 

It is actually 10 micrograms, not 10 grams. But it is still amazing that you can apparently buy samples of the FGF21 hormone online from Amazon. I'm not recommending it, however.

 

--Dean

[KHashmi317]

A few qualitative comments on the cold issue ....

 

I hate being cold! When I'm cold, I can't think of much else other than how to get warm. That's "dead time" in my book ;)

 

I hate the time lost dressing up and down to counteract what my body perceives as uncomfortable temperature. You might be in the middle of something (even an engaging philosophical thought) ... a shiver comes and -- bam! -- you're distracted away from that thought. Again: dead time when one has to engage in mindless manual labor of re- and de-layering!

[Sthira]

 

10 g for $70 on http://www.amazon.com/gp/aw/d/B010GG0KZW/ref=mp_s_a_1_2?qid=1453257934&sr=8-2&pi=SY200_QL40&keywords=FGF21&dpPl=1&dpID=51vexQ-cGfL&ref=plSrch

It is actually 10 micrograms, not 10 grams. But it is still amazing that you can apparently buy samples of the FGF21 hormone online from Amazon. I'm not recommending it, however.

 

--Dean

Oh well, then I guess I won't order 10 micrograms, not 10 grams to be delivered by an Amazon drone. :-(

[KHashmi317]

Just noticed Dean's subject header: "Cold Exposure & Other Mild Stressors for Increased Health & Longevity"...

Mild sleep restriction -- in and of itself (i.e. w/o CR) -- seems also to have some CR-like bennies. (check CR List Archives)

My criticisms of uncomfortably keeping cool for the sake of potential LE effects also hold for mild/deliberate sleep reduction.

Sleep, on heavy CR, can be short/incomplete. E.g., premature awakening; inability to re-sleep despite feeling groggy and sleep deprived. I have found that a short nap, no less than 6 hrs before bedtime, can be restorative (this is usually immediately following a meal: there's a sleepiness/siesta window there).

Sleep debt is something that is disruptive -- even dangerous -- throughout the wake cycle ... and that is QOL reduction ... i.e., "dead time."

Edited January 21, 2016 by KHashmi317

[Dean Pomerleau]

Khurram,

 

A few qualitative comments on the cold issue ....

 

I hate being cold! When I'm cold, I can't think of much else other than how to get warm. That's "dead time" in my book ;)

 

You'll like today's Dillbert cartoon then:

 

 

My wife always says she's cold. So much so that I gave her an electric shawl for her recent birthday (which she really like). Subjectively she's made miserable by the cold. The funny thing is that when we touch hands to compare our body temperatures, I'm almost always objectively colder than she is. But it doesn't bother me. I think I've trained myself to be indifferent to the cold, and now I find it refreshing and bracing rather than debilitating. 

 

Regarding sleep, I don't think I've seen the evidence that mild sleep restriction is beneficial and I'd be somewhat skeptical given all documented apparent downsides of lost sleep. Unfortunately the CR email list archives appear to be down for the count. 

 

But it is definitely true that CR in humans is frequently associated with sleep disturbances, or at least reduced hours spent sleeping, and the recent CR & Sleep Poll documents. I too have found a short "power nap" of about 20 minutes around mid-day makes me feel refreshed, and able operate effectively on what for me has lately become about 5:45-6h of nighttime sleep.

 

--Dean

[Gordo]

But in addition, cold exposure (66F vs controls at 75F for 12h) apparently upregulates FGF21 expression in people by 37%, and this increase in FGF21 predicted increase in 24h energy expenditure [2].

 

Finally, exercise has also been shown to increase the level of FGF21 in humans [3][4]. In fact, two weeks of treadmill exercise increased FGF21 levels by 66% in healthy young women tested in [3].

 

----------

[3] PLoS One. 2012;7(5):e38022. doi: 10.1371/journal.pone.0038022. Epub 2012 May 31.

 

Exercise increases serum fibroblast growth factor 21 (FGF21) levels.

 

Cuevas-Ramos D(1), Almeda-Valdés P, Meza-Arana CE, Brito-Córdova G, Gómez-Pérez

FJ, Mehta R, Oseguera-Moguel J, Aguilar-Salinas CA.

 

Free full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3365112/

 

 

It certainly seems like you get more bang for your buck from exercise (study focused on short duration, high intensity exercise (HIIT) in particular with otherwise sedentary people doing no other exercise).

 

I personally don't mind 66 degrees, could keep the thermostat there all winter. I can't see myself cooling the house to 66 all Summer long though (wastes a lot of energy).  But I do wonder, if you are just wearing extra layers of clothes, or burried under a big pile of blankets (when sleeping) do you really get the benefit of the cooler temps?  I do think I sleep more soundly in cooler temperatures.

[Dean Pomerleau]

Gordo,

 

[From PMID: 23667629] It certainly seems like you get more bang for your buck from exercise (study focused on short duration, high intensity exercise (HIIT) in particular with otherwise sedentary people doing no other exercise).

 

Yes, but that is for FGF21 only. There is much more going on with the benefits of cold exposure (and exercise) than raising FGF21. From the evidence above, it looks to me like cold exposure may actually extend lifespan, while exercise is not believed to.

 

But I do wonder, if you are just wearing extra layers of clothes, or buried under a big pile of blankets (when sleeping) do you really get the benefit of the cooler temps?

 

Almost certainly not. I'm working on a big post on this very topic, but as a preview, it appears you actually have to be cold (i.e. have reduced core body temperature) to benefit. Turning the thermostat down and bundling up almost certainly defeats the purpose.

 

--Dean

[KHashmi317]

Unfortunately the CR email list archives appear to be down for the count. 

I was just going to post on that.

There's some content I posted on the List that I thought could benefit from re-posting (on this forum).

Not sure how long the archs have been down or whether there are plans for re-up. It's important to have them back up ... 'cause even on lifelong CR, my memory banks are springing some leaks ;)

Edited January 22, 2016 by KHashmi317

[Dean Pomerleau]

Khurram,

 

Great profile picture - it's nice to see your face again after so many years!

 

Regarding the email list archives. I couldn't agree more. They are a treasure trove of wisdom and information. It will be tragedy if they are forever unavailable. I have several hundred megabytes of the archives thanks to James Caine, but only starting in 2008 and only in raw & unparsed format - very hard to search. But everything before that, when I, Sherm, you, Saul, Warren and others were most active on the list is entirely unavailable right now, at least as far as I can tell.   

 

Brian has mentioned several times they are working on making them available again, but it's been this way for quite a while now - many months at least.

 

--Dean

[KHashmi317]

 

Khurram,

 

Great profile picture - it's nice to see your face again after so many years!

 

Regarding the email list archives. I couldn't agree more. They are a treasure trove of wisdom and information. It will be tragedy if they are forever unavailable. I have several hundred megabytes of the archives thanks to James Caine, but only starting in 2008 and only in raw & unparsed format - very hard to search. But everything before that, when I, Sherm, you, Saul, Warren and others were most active on the list is entirely unavailable right now, at least as far as I can tell.   

 

 

That photo is from 2002. It's the only pose I could find to show all of me compressed in one small frame!

 

About the archs ... I don't get it??? I know that less than a year ago, I could access them FULLY (I think -- at least my legacy mails were in there). IAC, I hope we get them back. There's gold in them thar hills.

 

About cold exposure -- again, the archs would help as the topic was brought up several times -- but you bought up the Walford paper on hibernation and torpor.

And perhaps as importantly, that cold exposure doesn't produce benefits as a result of inducing a hibernation-like state of torpor and reduced metabolic rate, as previously thought (by Roy Walford and others, citation (35)) but quite the opposite. The benefit results from (or at least occur in the presence of) an increased metabolic rate exhibited by skinny CR mice housed in relatively cool conditions in order to maintain their body temperature: [...]

 

 

Recall however, at CRII, that Jamie Barger described "Calorie Restriction as a [potential] hibernation mimetic. "

 

 

Michael Rae noted that the LS curves of hibernating and CR animals were similar.

 

A few weeks ago the Cambridge Univ. weekly podcast of The Naked Scientists discussed The Hidden World of Hibernation.

http://nakeddiscovery.com/libsyn/Naked_Scientists_Show_16.01.19.mp3

 

 

Especially interesting is the segment starting: 39:04 - Dismantling brain cells:

 

 

Though the idea of a long sleep may sound pretty tempting, animals actually put themselves through an awful lot. They are continually cooling and reheating their bodies, putting huge stress on their organs, and some even make themselves diabetic. Hibernation is clearly no picnic, and things get even Neuronsworse as, in an attempt to save energy, animals will dismantle the synapses in their brains. These are the parts of the neuron that send and receive signals and without them we’re all pretty useless. But what’s even more amazing is that when it’s time to “wake up”  they’ll put them back together again, just as they were. Professor Giovanna Mallucci is a clinical neuroscientist at Cambridge University and she explains to Connie Orbach how this actually works.

 

Giovanna -  I think you’ve heard already from our other speakers, that there’s lots of processes that slow down and are shut down for hibernation including metabolism.  And one way to save energy is to stop the brain using its energy and the dismantling of synaptic connections between brain cells is a way of doing that.  What happens is, on cooling there is a retraction of what we call the “dendritic arbour”, you know all the connections and branches of a brain cell that’s connecting to another and the actual contacts - it’s like unplugging a plug from its socket, they are just removed so that no energy flows.  When they rewarm there’s a signal to reconnect these structures; how that exactly happens is absolutely not known and very, very interesting to us but we do know a lot about the processes that drive that regenerative capacity.

 

Connie - Is this happening all over the brain?

 

Giovanna - Yes, it’s happening all over the brain and all of us all the time.  So there’s a balance between pruning and generation or regeneration to maintain a sort of status quo and learning and memory need new synapses and then you prune and get rid of all your excess synapses when you sleep and other conditions.  But the capacity for regenerating synapses and refreshing them is part of repair and it’s called “structural synaptic plasticity.”

 

Connie - So let me just get this right. So what’s happening with animals in hibernation is a much more extreme version of actually something that’s happening all the time in humans and animals?

 

Giovanna - Correct, that’s exactly right.

 

Connie - So how have you been using this then in your work?

 

Giovanna -   So we know that in neurodegenerative diseases like Alzheimer’s, which is the prototypical disease but also many of the others.  The earliest thing that happens, before you get the brain cell degeneration, is that synapses are lost and as synapses are lost memory goes down - what we call cognitive function goes down, and it’s just not clear why this is early loss of synapses which is such an important stage in these diseases, and it’s important a) because it give you symptoms and b) because it's reversible.  So that’s the stage before the brain cells have died, before the neurons have died when, actually, if you can increase synapse number you can restore memory so it’s a very attractive, targetable point of intervention.  And our starting hypothesis was that the reason that synapses are lost early in Alzheimer’s disease and early in Parkinson’s disease and other disorders is because there’s a failure of this regenerative capacity that is part of our normal structural plasticity.  We used hibernation or induced laboratory hibernation in mice to test the ability of synapses to regenerate themselves in mouse neurodegeneration models.

 

Connie - And what did you find out - what’s happening?

 

Giovanna - So first of all we found very interestingly that mice which don’t normally hibernate, can hibernate in all the ways that you would normally expect.  So if you cool them: they’ll drop their body temperature, they’ll dismantle their synapses and they’ll go into torpor and then, when you re-warm them, they come completely back to normal again.  And what we found out was that normal mice dismantle and reassemble their synapses but the mice that we used that had neurodegeneration models - that’s Alzheimer type mice, and mice with prion disease - that’s another neurodegenerative disease.  They failed to reassemble their synapses so they could unplug the plugs but they couldn’t put them back in again and this lack of degenerative capacity gives us a good idea of why there’s such an early loss in synapses.

 

Connie - Did you get a bit deeper into this?  Did you get to see the protein that’s involved - is that right?

 

Giovanna - Yes we did. So hibernating and cooling does two things to you: it shuts down metabolism and it shuts down protein synthesis, but there’s a group of proteins that are upregulated and these are called “cold-shock proteins,” and they’re a relatively new family of proteins.  And one of these which is called “RBM3”, which is RNA Binding Motif Protein 3, is highly expressed in the brain and by being upregulated during hibernation that protein keeps a number of really important critical Messenger RNAs, that you need for survival, ready to make into proteins when you wake up.  And we found out that RBM3 is failing in the Alzheimer’s brain, and if we put it back in, we can rescue them.

 

Connie - So you found this protein, RBM3 - where do you go now?

 

Giovanna - So, we didn’t find the protein; I mean the proteins a known cold shock protein.  What we’ve done is associate it with the failure of structural plasticity in neurodegenerative disease in Alzheimer type mouse models and what we now want to do is understand the relevance for human disease.  Because what we found in the mice is that if you put the protein back in it’s incredibly protective, it gives them new synapses, it stops them getting neurodegeneration, it stops them getting memory loss, and it protects them in the long term and you can do that by either cooling the mice early to boost their indodgenous or their own RBM3 levels, or by putting it in artificially.  So now, obviously, this is a way in for neuroprotection for human disease but cooling itself is not realistic or practical in the long term.  It is used medically; it’s used in newborn babies that have had hypoxic damage; it’s used in post-stroke and it’s used in cardiac surgery, and in many forms of neurosurgery.  So we thinks that that’s acting through RBM3 and our ideal would be to be able to manipulate RBM3 levels for protection without having to cool.

[Dean Pomerleau]

Thanks Khurram!

 

Regarding the archives - yes it wasn't too long ago that they were available. And as I understand it the information is definitely not lost. Perhaps Brian or Tim could give us an update and the plan (if any) to bring them back on-line.

 

Regarding cold exposure (CE).  I think I agree with you and the evidence you share regarding CE and it relationship to hibernation/turpor. H/T have both 'passive' and 'active' mechanisms and benefits.

 

As an example of passive benefits, lower (body) temperature reduces the rate of certain harmful chemical processes in the body - perhaps processes like protein crosslinking & glycation.

 

Active mechanisms (that actually require more fuel rather than less) might be the uncoupling of mitochondria energy production to generate heat rather than ATP, but in the process also making the mitochondrial energy production 'cleaner' (fewer free radicals generated) as a side benefit.

 

I see CE as sort of like CR and exercise, which are both 'master stressors', that put pressure on the organism to hunker down and clean up its act to survive the ordeal. The organism responds to such challenges in a multitude of beneficial and yet-to-be-fully-elucidated ways, which improve health & longevity, at least up to a point.

 

But beyond some point, the stress becomes too great to cope with and does permanent damage. So starving to the point at which the body catabolizes it's own vital organs, or running an  ultramarathon at a pace that damages heart tissue, or freezing to the point that one's heart stops beating, are all unlikely to be helpful   .  The fact that hibernating animals don't live longer than "warm" animals doesn't surprise me. The conditions and impact on the body of true hibernation may be too extreme and prolonged a stressor to be beneficial, like starvation or ultramarathoning.

 

Thanks for sharing that interview. I'd never heard of "cold shock proteins" or RBM3. Fascinating! It looks like one more mechanism by with CE might be beneficial, in this case for cognitive function by preserving synapses and neural plasticity.

 

In fact the researcher seems to have an attitude that's very similar to CR researchers, when he says:

 

Because what we found in the mice is that if you put the protein back in it’s incredibly protective, it gives them new synapses, it stops them getting neurodegeneration, it stops them getting memory loss, and it protects them in the long term and you can do that by either cooling the mice early to boost their [edo]genous or their own RBM3 levels, or by putting it in artificially.  So now, obviously, this is a way in for neuroprotection for human disease but

cooling itself is not realistic or practical in the long term...

 

In other words, it's the same story we hear from CR researchers all the time - "CR has amazing benefits but we can't expect people to actually do it, so we're going to try to find a pill to mimic it.'

 

In the meantime, some of us are willing and able to actually do it. 

 

--Dean

[Saul]

Hi Dean and Khurram!

 

I always was fascinated by the "rats with cold feet" study -- it's fascinating to see that the advantages of cold exposure could be due to the raising of the FGF21 protein -- which is also raised by IF (and, I'd guess, standard CR) and exercise.  My intuition:  All of these may extend mean, and maybe even maximal, lifespan (in the case of "exercise", it probably matters "what kind".  I'd guess that aerobic, but not strengthening, exercise is the "good" kind).

 

Khurram, I don't like being cold either -- but it's unavoidable in Rochester, NY -- and it's nice to see that, together with CR, it's probably good for you.

 

 

It will be fascinating to see further info on the role of the FGF21 protein.

 

In the meantime, I strongly agree with Dean -- it's not a good idea to supplement FGF21.

 

 -- Saul