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Cold Exposure & Other Mild Stressors for Increased Health & Longevity


Dean Pomerleau
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On 6/9/2021 at 4:00 PM, Saul said:

The takeaway:  Life expectancy is longer in States with Higher Income.

True. Medical care has advanced considerably, at a price.

Yet the Blue Zones are all in temperate to warm climates, often dirt poor, like Sardinia and Okinawa.

The oldest person born in the North I could find was Christian Mortensen, but he actually spent most of his life in balmy California....

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BAT Hypertrophy after CR Correlates with Lifespan Benefits

I've suggested repeatedly on this thread (e.g. here, herehere and here) that there may be a synergy between CR and cold exposure (CE) when it comes to lifespan and healthspan. In fact, I've said that the benefits of CR may require the simultaneous exposure to cold environmental conditions.

This new study [1] posted by Al (thanks Al!) seems like pretty good evidence to support this hypothesis, and that the effect is mediated by thermogenic Brown Adipose Tissue (BAT).

First a little background. We've discussed several times in this thread and elsewhere (e.g. here) the evidence that CR works to extend lifespan in some strains of mice, while shortening lifespan in others. Here is the graph from [2] of the impact of CR on lifespan of various strains of female mice:

20210716_135142.jpg

Some strains, like 89 (green highlight above) have their lifespan dramatically extended by 40% CR. Some, like strain 114 (red highlight) live shorter lives when subjected to 40% CR. And some, like strain 48 (yellow), don't show much difference in lifespan on 40% CR.

It was subsequently shown in [3] (by the same authors as [2]) that in these same strains of mice, those strains that maintain their body temperature better when exposed to "normal" (i.e. chilly for mice, ~72degF) housing conditions were the ones that benefited from CR. Obviously that is a tantalizing hint that the ability to boost thermogenic BAT when subjected to CR + CE may be key for extending lifespan at least in these strains, as I discussed here.

Further evidence for the importance of BAT when it comes to longevity in the face of CR + CE was demostrated in [4] (discussed here), which showed that BAT was the only tissue whose mass was increased when subjected to CR. As you can see from this table from [4], every other tissue except the brain and a few muscles (which stayed the same) shrunk in 40% CR mice relative to its size under ad lib feeding at both 6 months and 26 months of age, while BAT mass more than doubled:

Screenshot_20210716-143606_Chrome.jpg

 

Now we come to this new study [1], which looked at three of the strains of mice from the original study [2] whose response to CR differed - specifically the strains of mice I highlighted above with green (longevity benefitted from CR), yellow (no change in longevity from CR) and red (shortened longevity from CR). Note the three strains had similar lifespans when fed AL; it was only when subjected to CR that their lifespans diverged.

So what did they find differed between these strains besides longevity? Most relevant for this thread and my hypothesis, they found that in the green, long-lived strain and to a lesser extent the yellow strain, BAT mass was increased when the mice were subjected to CR + CE, while in the red strain whose lifespan was shortened by CR, their BAT mass was unchanged relative to AL. Below is the (color coded) set of graphs from [1]. All three strains lost weight on CR (graph A), but only the green strain dramatically boosted BAT mass as a percent of body mass (gragh D) as a result of CR:

20210716_145722.jpg 

So once again we see the importance for longevity of preserving or even increasing BAT when subjected to CR + CE.

In this rather geeky and speculative post, I hypothesized that in order to stay warm, strains of mice that don't increase BAT when subjected to CR + CE have to maintain lots of highly unsaturated long-chain fatty acids in their cell and especially mitochondrial membranes (contra the usual effect of CR which is to increase membrane saturation), thereby making their membranes "leakier" to protons (which generates heat) but also making said membranes more susceptible to peroxidation, thereby harming their longevity. In contrast, strains which boost BAT when subjected to CR + CE can keep warm via BAT-thermogenesis and so can keep their membranes "tight" (i.e. saturated) and therefore less susceptible to peroxidation, increasing lifespan.

In (qualified) support of this hypothesized mechanism, the authors of [1] found that only green strain (but not the red strain) showed the usual CR-induced increase in membrane saturation at least in the tissue they measured (white adipose tissue).

One surprise in [1] was that only the red strain showed improved glucose tolerance when subjected to CR, which seems to contradict lots of evidence from elsewhere (and personal experience) that cold exposure and extra BAT improves glucose metabolism.

But whatever the mechanism, [1] provides further evidence that the ability to boost BAT when subjected to CR + CE is integral to the life-extending effect of the combination, and it goes without saying (since I've said it so many times before :-)), that CR in rodents only appears to extend longevity when combined with CE.

--Dean

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[1] Strain-specific metabolic responses to long-term caloric restriction in female ILSXISS recombinant inbred mice.
Mulvey L, Wilkie SE, Griffiths K, Sinclair A, McGuinness D, Watson DG, Selman C.
Mol Cell Endocrinol. 2021 Jul 8:111376. doi: 10.1016/j.mce.2021.111376. Online ahead of print.
PMID: 34246728 Review.
Abstract
The role that genetic background may play in the responsiveness of organisms to interventions such as caloric restriction (CR) is underappreciated but potentially important. We investigated genetic background on a suite of metabolic parameters in female recombinant inbred ILSXISS mouse strains previously reported to show divergent lifespan responses to 40% CR (TejJ89-lifespan extension; TejJ48-lifespan unaffected; TejJ114-lifespan shortening). Body mass was reduced across all strains following 10 months of 40% CR, although this loss (relative to ad libitum controls) was greater in TejJ114 relative to the other strains. Gonadal white adipose tissue (gWAT) mass was similarly reduced across all strains following 40% CR, but brown adipose tissue (BAT) mass increased only in strains TejJ89 and TejJ48. Surprisingly, glucose tolerance was improved by CR only in TejJ114, while strains TejJ89 and TejJ114 were relatively hyperinsulinemic following CR relative to their AL controls. We subsequently undertook an unbiased metabolomic approach in gWAT and BAT tissue from strains TejJ89 and TejJ114 mice under AL and 40% CR. gWAT from TejJ89 showed a significant reduction in several long chain unsaturated fatty acids following 40% CR, but gWAT from TejJ114 appeared relatively unresponsive to CR, with far fewer metabolites changing. Phosphatidylethanoloamine lipids within the BAT were typically elevated in TejJ89 following CR, while some phosphatidylglycerol lipids were decreased. However, BAT from strain TejJ114 again appeared unresponsive to CR. These data highlight strain-specific metabolic differences exist in ILSXISS mice following CR. We suggest that precisely how different fat depots respond dynamically to CR may be an important factor in the variable longevity under CR observed in these mice.
Keywords: Dietary restriction; Genetic heterogeneity; Metabolomics; White adipose tissue; brown adipose tissue.

 

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[2] Exp Gerontol. 2010 Sep;45(9):691-701. doi: 10.1016/j.exger.2010.04.008. Epub 

2010 May 7.

Genetic dissection of dietary restriction in mice supports the metabolic 
efficiency model of life extension.

Rikke BA(1), Liao CY, McQueen MB, Nelson JF, Johnson TE.

Author information:
(1)Institute for Behavioral Genetics, University of Colorado at Boulder, 
Boulder, CO 80309, USA. rikke@colorado.edu

Dietary restriction (DR) has been used for decades to retard aging in rodents, 
but its mechanism of action remains an enigma. A principal roadblock has been 
that DR affects many different processes, making it difficult to distinguish 
cause and effect. To address this problem, we applied a quantitative genetics 
approach utilizing the ILSXISS series of mouse recombinant inbred strains. 
Across 42 strains, mean female lifespan ranged from 380 to 1070days on DR (fed 
60% of ad libitum [AL]) and from 490 to 1020days on an AL diet. Longevity under 
DR and AL is under genetic control, showing 34% and 36% heritability, 
respectively. There was no correlation between lifespans on DR and AL; thus 
different genes modulate longevity under the two regimens. DR lifespans are 
significantly correlated with female fertility after return to an AL diet after 
various periods of DR (R=0.44, P=0.006). We assessed fuel efficiency (FE, 
ability to maintain growth and body weight independent of absolute food intake) 
using a multivariate approach and found it to be correlated with longevity and 
female fertility, suggesting possible causality. We found several quantitative 
trait loci responsible for these traits, mapping to chromosomes 7, 9, and 15. We 
present a metabolic model in which the anti-aging effects of DR are consistent 
with the ability to efficiently utilize dietary resources.

Copyright 2010 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.exger.2010.04.008
PMCID: PMC2926251
PMID: 20452416 [Indexed for MEDLINE]

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

[3] Aging Cell. 2011 Aug;10(4):629-39. doi: 10.1111/j.1474-9726.2011.00702.x. Epub

2011 Apr 25.

Fat maintenance is a predictor of the murine lifespan response to dietary
restriction.

Liao CY(1), Rikke BA, Johnson TE, Gelfond JA, Diaz V, Nelson JF.

Author information: 
(1)Department of Physiology, University of Texas Health Science Center, San
Antonio, TX 78229, USA.

Dietary restriction (DR), one of the most robust life-extending manipulations, is
usually associated with reduced adiposity. This reduction is hypothesized to be
important in the life-extending effect of DR, because excess adiposity is
associated with metabolic and age-related disease. Previously, we described
remarkable variation in the lifespan response of 41 recombinant inbred strains of
mice to DR, ranging from life extension to life shortening. Here, we used this
variation to determine the relationship of lifespan modulation under DR to fat
loss. Across strains, DR life extension correlated inversely with fat reduction, 
measured at midlife (males, r= -0.41, P<0.05, n=38 strains; females, r= -0.63,
P<0.001, n=33 strains) and later ages. Thus, strains with the least reduction in 
fat were more likely to show life extension, and those with the greatest
reduction were more likely to have shortened lifespan. We identified two
significant quantitative trait loci (QTLs) affecting fat mass under DR in males
but none for lifespan, precluding the confirmation of these loci as coordinate
modulators of adiposity and longevity. Our data also provide evidence for a QTL
previously shown to affect fuel efficiency under DR. In summary, the data do not 
support an important role for fat reduction in life extension by DR. They suggest
instead that factors associated with maintaining adiposity are important for
survival and life extension under DR.

© 2011 The Authors. Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society
of Great Britain and Ireland.

DOI: 10.1111/j.1474-9726.2011.00702.x 
PMCID: PMC3685291
PMID: 21388497  [Indexed for MEDLINE]

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

[4] 

Mech Ageing Dev. 2005 Jun-Jul;126(6-7):783-93. Epub 2005 Mar 16.
 
Energy expenditure of calorically restricted rats is higher than predicted from
their altered body composition.
 
Selman C(1), Phillips T, Staib JL, Duncan JS, Leeuwenburgh C, Speakman JR.
 
Author information: 
(1)University of Florida, Department of Aging and Geriatric Research, College of 
Medicine, Gainesville, 32608, USA. c.selman@ucl.ac.uk
 
Debate exists over the impact of caloric restriction (CR) on the level of energy 
expenditure. At the whole animal level, CR decreases metabolic rates but in
parallel body mass also declines. The question arises whether the reduction in
metabolism is greater, smaller or not different from the expectation based on
body mass change alone. Answers to this question depend on how metabolic rate is 
normalized and it has recently been suggested that this issue can only be
resolved through detailed morphological investigation. Added to this issue is the
problem of how appropriate the resting energy expenditure is to characterize
metabolic events relating to aging phenomena. We measured the daily energy
demands of young and old rats under ad libitum (AD) food intake or 40% CR, using 
the doubly labeled water (DLW) method and made detailed morphological examination
of individuals, including 21 different body components. Whole body energy demands
of CR rats were lower than AD rats, but the extent of this difference was much
less than expected from the degree of caloric restriction, consistent with other 
studies using the DLW method on CR animals. Using multiple regression and
multivariate data reduction methods we built two empirical predictive models of
the association between daily energy demands and body composition using the ad
lib animals. We then predicted the expected energy expenditures of the CR animals
based on their altered morphology and compared these predictions to the observed 
daily energy demands. Independent of how we constructed the prediction, young and
old rats under CR expended 30 and 50% more energy, respectively, than the
prediction from their altered body composition. This effect is consistent with
recent intra-specific observations of positive associations between energy
metabolism and lifespan and theoretical ideas about mechanisms underpinning the
relationship between oxygen consumption and reactive oxygen species production in
mitochondria.
 
PMID: 15888333
 
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Excess dietary carbohydrate affects mitochondrial integrity as observed in brown adipose tissue.
Waldhart AN, Muhire B, Johnson B, Pettinga D, Madaj ZB, Wolfrum E, Dykstra H, Wegert V, Pospisilik JA, Han X, Wu N.
Cell Rep. 2021 Aug 3;36(5):109488. doi: 10.1016/j.celrep.2021.109488.
PMID: 34348139
https://www.cell.com/cell-reports/pdf/S2211-1247(21)00915-3.pdf
Abstract
Hyperglycemia affects over 400 million individuals worldwide. The detrimental health effects are well studied at the tissue level, but the in vivo effects at the organelle level are poorly understood. To establish such an in vivo model, we used mice lacking TXNIP, a negative regulator of glucose uptake. Examining mitochondrial function in brown adipose tissue, we find that TXNIP KO mice have a lower content of polyunsaturated fatty acids (PUFAs) in their membrane lipids, which affects mitochondrial integrity and electron transport chain efficiency and ultimately results in lower mitochondrial heat output. This phenotype can be rescued by a ketogenic diet, confirming the usefulness of this model and highlighting one facet of early cellular damage caused by excess glucose influx.
Keywords: BAT; PUFA; TXNIP; cold stress; glucose; ketogenic diet; lipid; mitochondria.

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This paper shows brown fat activity is higher in the morning. Taking a cold shower or eating breakfast earlier in the day can trigger brown fat function much more than in the evening.

https://www.nature.com/articles/s41366-021-00927-x

Abstract

Background/objectives

Disturbed circadian rhythm is associated with an increased risk of obesity and metabolic disorders. Brown adipose tissue (BAT) is a site of nonshivering thermogenesis (NST) and plays a role in regulating whole-body energy expenditure (EE), substrate metabolism, and body fatness. In this study, we examined diurnal variations of NST in healthy humans by focusing on their relation to BAT activity.

Methods

Forty-four healthy men underwent 18F-fluoro-2-deoxy-D-glucose positron emission tomography and were divided into Low-BAT and High-BAT groups. In STUDY 1, EE, diet-induced thermogenesis (DIT), and fat oxidation (FO) were measured using a whole-room indirect calorimeter at 27 °C. In STUDY 2, EE, FO, and skin temperature in the region close to BAT depots (Tscv) and in the control region (Tc) were measured at 27 °C and after 90 min cold exposure at 19 °C in the morning and in the evening.

Results

In STUDY 1, DIT and FO after breakfast was higher in the High-BAT group than in the Low-BAT group (P < 0.05), whereas those after dinner were comparable in the two groups. FO in the High-BAT group was higher after breakfast than after dinner (P < 0.01). In STUDY 2, cold-induced increases in EE (CIT), FO, and Tscv relative to Tc in the morning were higher in the High-BAT group than in the Low-BAT group (P < 0.05), whereas those after dinner were comparable in the two groups. CIT in the High-BAT group tended to be higher in the morning than in the evening (P = 0.056).

Conclusion

BAT-associated NST and FO were evident in the morning, but not in the evening, suggesting that the activity of human BAT is higher in the morning than in the evening, and thus may be involved in the association of an eating habit of breakfast skipping with obesity and related metabolic disorders.

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I know we talked about this study long ago, but I searched and didn't see this particular analysis (from 2016) posted here before:

The 'Wim Hof Method' - Effective? What Science Can Tell Us

https://suppversity.blogspot.com/2016/06/the-wim-hof-method-effective-what.html

Its a very nice detailed breakdown of this study:  "Matthijs Kox and colleagues from the Nijmegen Institute for Infection, Inflammation and Immunity, the Radboud University, the Yale University School of Medicine (Kox. 2014) published a study with the not so telling title "Voluntary activation of the sympathetic nervous system and attenuation of the innate immune response in humans" in the peer-reviewed scientific journal PNAS."

Could have useful practical application perhaps for some people or some specific circumstance.

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Live fast, die young? Or live cold, die old?

[The researchers]  found that body temperature exerts a greater effect on lifespan than metabolic rate.

 "live fast, die young" …  in biology it comes from the observation that animals with high metabolic rates ("living fast") tend to die sooner than those with slow metabolism.

[However] exercise increases metabolism, but on average it seems to make people live a little longer.

researchers utilized an unusual situation where metabolic rate and body temperature move in opposite directions to try to determine which factor is more important.

When mice and hamsters are exposed to high temperatures, at the top of their thermoneutral zone, their metabolism falls while their body temperature goes up. "We found that exposing the rodents to these conditions shortened their lifespans. Lower metabolism didn't lengthen their lives, but higher temperatures shortened it”

 In this study, the researchers used small fans to blow air over the mice and hamsters exposed to high temperatures. This didn't affect their metabolism, but it prevented them from having high body temperatures. This situation reversed the impact of high ambient temperature on their lifespan.

We separated the effect of body temperature on lifespan from metabolic rate in two species of small rodents exposed to high temperatures. We are excited about the findings, particularly that using small fans to blow air over the animals reversed the effect of high ambient  temperature on lifespan by decreasing body temperature without changing metabolic rate

separated the effect of body temperature on lifespan from metabolic rate in two species of small rodents exposed to high temperatures

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Article from her website referenced at the end of the video:

https://www.foundmyfitness.com/topics/cold-exposure-therapy

Introduction

The use of cold exposure to promote good health is an ancient practice, dating back many centuries. In modern times, cold exposure is used primarily to reduce muscle soreness and promote muscle recovery after physical activity. However, regular cold exposure may also improve glucose and lipid metabolism, decrease inflammation, enhance immune function, and improve cognitive performance. The beneficial effects of cold exposure may be due to hormesis, a favorable biological response to a mild stressor. Hormesis triggers protective mechanisms that provide protection from future, more harmful stressors.

Despite the presumed benefits associated with cold exposure, it does pose some risks, especially in unsupervised or uncontrolled conditions. See our overview of cold exposure safety concerns at the end of this article.

This article provides an overview of cold exposure modalities as well as the physiological responses, health effects, and safety concerns associated with the practice.

Cold exposure modalities

Common cold exposure modalities include cold water immersion, local cryotherapy, and whole-body cryotherapy. Cold-water immersion involves submerging one's body in water typically at or below 59°F (15°C). Local cryotherapy generally involves placing ice packs on specific areas of the body, such as joints or muscles. Whole-body cryotherapy involves exposure to cold air for a few minutes at temperatures as low as -289°F (-178°C), typically in a cryotherapy chamber, wearing protective garments on the extremities. Cryotherapy chambers must be colder than water because thermal conductivity, the rate at which heat is transferred, differs between water and air. The thermal conductivity of water is 25 times greater than air, so humans lose body heat up to five times more quickly in water compared to the same temperature in air.[1][2]

Physiological responses to cold exposure

Exposure to cold temperatures induces a range of acute physiological responses, collectively referred to as the cold shock response. The goal of the cold shock response is to reduce heat loss and increase heat production.[3][4]

ColdShock_IceBath_v2.jpg

Exposure to cold temperatures induces a range of acute physiological responses, collectively referred to as the cold shock response.

With repeated exposure, the body becomes habituated to cold, diminishing the cold shock response.[5][6][7] A study in healthy young men investigated the effects of habituation to the cold shock response. Participants underwent brief cold-water immersion sessions at 50°F (10°C) on the first and fifth day of the study, and immersion sessions at 59°F (15°C) on the intervening days. On the fifth day, the cold-exposed group showed a 49 percent decrease in respiratory frequency and a 15 percent decrease in heart rate response to 50°F (10°C) exposure compared to the first day at the same temperature.[8]

Norepinephrine release

Integral to the cold shock response is the release of norepinephrine, a hormone and neurotransmitter produced in the adrenal glands and some regions of the brain. Norepinephrine increases heart rate, activates thermogenesis (the production of heat), constricts blood vessels, and modulates immune function.[9][10] Norepinephrine release can also activate peroxisome proliferator-activated receptor gamma coactivator 1-alpha, or PGC-1 alpha, a key regulator of genes involved in energy metabolism.[11][12] PGC-1 alpha participates in glucose and fatty acid metabolism, muscle fiber remodeling, mitochondrial biogenesis (the production of new mitochondria), and thermoregulatory function.[13]

A study in healthy young men investigated the effects of hormone release after hour-long immersion sessions in water temperatures of approximately 90°F (32°C), 68°F (20°C), and 57°F (14°C), with one week separating each exposure. Whereas water immersion at warmer temperatures (90°F [32°C)]) and (68°F [20°C]) did not activate norepinephrine release, immersion at a colder temperature (57°F [14°C]) increased norepinephrine by 530 percent, dopamine by 250 percent, and energy expenditure by 350 percent, compared to pre-immersion levels.[14] A separate study found that immersion in cold water at 50°F (10°C) for an hour increased plasma norepinephrine by approximately 84 percent (compared to immersion for just two minutes), suggesting that exposing the body to cold for prolonged periods may elicit greater norepinephrine release.[15]

However, long cold exposure durations of one hour may not necessarily be required to induce norepinephrine release. A long-term study compared healthy women who immersed themselves in cold water at 40°F (4.4°C) for 20 seconds to those who received whole-body cryotherapy for two minutes at -166°F (-110°C). In both groups, plasma norepinephrine increased 200 to 300 percent. Those levels dropped, however, over the course of an hour after the exposure.[16] Habituation does not appear to affect the release of norepinephrine, but it does increase the activity of brown adipose tissue (described below), which is involved in nonshivering thermogenesis (described below).[16][17]

See the section "Cold exposure affects aspects of brain function" below for information about the role of norepinephrine in brain health.

Cold shock protein induction

During the cold shock response, cell membranes lose their fluidity, nucleic acids and proteins become destabilized, and protein synthesis stalls due to impaired ribosomal function.[18] Cold shock proteins, a large family of highly conserved proteins that are induced by various cellular stressors such as cold exposure, DNA damage, and hypoxia, ameliorate the harmful effects of cold.[19]

Notable cold shock proteins include cold‐inducible RNA binding protein, which promotes cell survival and activates antioxidant enzymes under conditions of mild hypothermia (89.6°F [32°C]), and RNA binding motif 3, or RBM3, which may be neuroprotective.

RBM3 binds to RNA to increase protein synthesis at neuronal dendrites, a part of the neuron that communicates with synapses, thus facilitating regeneration of damaged neurons.[20][21][22] [23][24] [25][26] See the section "Cold exposure affects aspects of brain function" below for more information about RBM3.

Mitochondrial biogenesis

Mitochondrial biogenesis is the process by which new mitochondria are produced. It is one of the principal beneficial adaptations to endurance exercise.[27][28] Many factors can activate mitochondrial biogenesis, including exercise, cold shock, heat shock, fasting, and ketones. As mentioned above, mitochondrial biogenesis is regulated by the transcription factor PGC-1α.

Increased mitochondrial biogenesis within skeletal muscle is associated with greater aerobic capacity and performance and reduced risk factors for various diseases.[29] Cold water immersion after endurance exercise increases PGC-1 alpha concentrations in skeletal muscle, and studies in both mice and humans suggest that mitochondrial biogenesis is increased upon cold exposure.[30][11][31][32]

For example, a study in healthy young men found that post-exercise cold water immersion increased several mitochondrial proteins in skeletal muscle. Within three minutes of completing vigorous aerobic exercise, the men immersed one leg in a 50°F (10°C) water bath for 15 minutes while keeping their other leg at room temperature without cooling treatment. Levels of p38 MAPK and AMPK (proteins involved in cellular signaling of mitochondrial biogenesis), PGC-1 alpha, and mitochondrial respiratory complex proteins 1 and 3 increased in the cold-exposed leg, compared to the one at room temperature.[12]

Thermogenesis

Cold exposure increases metabolic heat production through a process called thermogenesis. There are two types of thermogenesis: shivering and nonshivering.

Shivering thermogenesis, as its name implies, involves shivering to produce heat. During shivering, skeletal muscles undergo repeated, rapid contractions that produce little net movement and instead, produce heat.[33]

Nonshivering thermogenesis generates heat in the absence of shivering by unique mechanisms in both skeletal muscle and adipose (fat) tissue depots. These processes involve uncoupling electron transport from ATP synthesis and repetitive, non-productive transport of ions across the adipose cell membrane.[34] [35][36]

Brown adipose tissue activation

Mammals have three types of adipose (fatty) tissue – white, brown, and beige – and they play different roles in the body in terms of heat production.

The primary roles of white fat are the storage of excess lipids in the form of triglycerides and the release of free fatty acids for energy. The primary role of brown fat is thermogenesis.[37] Beige fat, which resides within white fat tissue stores, can adopt either storage or thermogenic properties based on environmental conditions.[38][39] Brown and beige fat are responsible for nonshivering thermogenesis. Rodents possess both brown and beige fat cells, while humans are thought to have beige fat cells primarily. The remainder of this article will use the term "brown fat" to refer to thermogenic tissues.

Early research suggested that brown fat was present only in newborns where it served as a means to protect against heat loss. However, recent research has identified active brown fat in adults, typically following cold exposure. For example, a study in which healthy young men were exposed to cold for two hours a day for 20 days found that brown fat volume increased 45 percent and cold-induced total brown fat oxidative metabolism increased more than twofold.[17] These findings suggest that cold exposure can increase brown fat activity and may increase energy expenditure to improve metabolic health.

Cold exposure also increases brown fat activity in people with little to no detectable brown fat mass. In a study involving healthy men who were exposed to warm or cold temperatures for two hours, researchers identified cold-activated brown fat in approximately half of the participants but not in the remainder. At 81°F (27°C), energy expenditure differed little among the two groups. But after two hours of cold exposure at 66°F (19°C), energy expenditure increased in both groups, even though muscle shivering among the participants was negligible. Cold-induced thermogenesis was 252 calories per day in the brown fat-positive men and 78.4 calories per day in the brown fat-negative men. The researchers posited that the increase in energy expenditure in the brown fat-negative men was attributable to previously undetected brown fat or separate thermogenic mechanisms.[40]

The researchers also measured repeated cold exposure in a subset of the men identified as having little to no brown fat activity. Half of the participants were exposed to cold at 63°F (17°C) for two hours every day for six weeks while the others maintained their usual lifestyles without cold exposure. Among those exposed to cold, thermogenesis increased by approximately 58 percent compared to baseline levels, coinciding with a loss of approximately 1.5 pounds (0.7 kilograms) in fat mass. None of these changes were observed in the non-cold-exposed group.[40] The continuous activation of brown fat may aid in fat loss, but more studies are needed to determine the extent to which brown fat can be activated to achieve clinical improvements in weight loss.

The activation of brown fat upon cold exposure may improve glucose and insulin sensitivity, increase fat utilization, and protect against diet-induced obesity, however. Studies in animals and humans have indicated that brown fat can improve glucose and insulin sensitivity, increase fat oxidation, and protect against diet-induced obesity.[41][42] In humans, brown fat typically decreases with percent body fat and age, whereas brown fat typically increases with a higher resting metabolic rate.[43][44][45] Cold exposure also increases brown fat volume, drives glucose uptake, and increases oxidative metabolism in brown fat.[46][47][48][49] Cold-induced glucose uptake in brown fat exceeds the rate of insulin-stimulated glucose uptake in skeletal muscle in healthy humans.[50][51] These findings have made brown fat an exciting therapeutic target for the treatment of obesity and obesity-related disorders.

Brown fat may also improve whole-body glucose utilization and insulin sensitivity in humans. In a study involving healthy young men (with or without detectable brown adipose tissue), cold exposure increased resting energy expenditure by 15 percent only in those with detectable brown fat, compared to thermoneutral conditions. This increase was primarily due to the oxidation of plasma-derived glucose (30 percent contribution) and fatty acids (70 percent contribution). Under thermoneutral conditions, both groups displayed normal insulin-induced whole-body glucose disposal. However, after six hours of cold exposure, only the brown fat detectable group had a further increase in glucose utilization when infused with insulin, indicating that brown fat plays a role in glucose utilization.[52]

General health effects associated with cold exposure

A growing body of evidence suggests that cold exposure affects multiple organ systems, eliciting beneficial effects on aspects of metabolic, cardiovascular, immune, and neurocognitive health, among others.

Metabolic health

The activation of nonshivering thermogenesis in people with obesity or type 2 diabetes may be an effective therapeutic strategy to aid in weight loss and improve metabolic health.[53] People with higher percent body fat typically have less brown fat; however, cold exposure increases brown fat volume and activity in people with high body fat.[54]

A study found that men with type 2 diabetes and overweight had improved insulin sensitivity after cold exposure. The men's brown fat volume and metabolic activity increased, but the levels were much lower than those typically seen in healthy people. The men's peripheral insulin sensitivity increased by approximately 43 percent, and in turn, skeletal muscle glucose uptake increased.[55]

A separate study in men with obesity found that brown fat volume was associated with increased fat mobilization and oxidation and corresponded to cold-induced changes in whole-body free fatty acid oxidation and lipolysis (release of fatty acids), signifying increased mobilization of lipids from peripheral tissues and utilization of lipids primarily in brown fat. After five hours of cold exposure, circulating free fatty acid levels increased compared to levels at thermoneutral conditions. However, the day after cold exposure, the men had decreased fasting triglyceride levels and very-low-density lipoprotein levels, suggesting that cold exposure may exert long-term beneficial alterations in lipid metabolism.[56]

In healthy adults, brown fat appears to have marked effects on glucose metabolism independent of age, sex, and percent body fat. A study in which participants intermittently put their feet on an ice block wrapped in cloth while sitting in a cold room evaluated the effects of cold exposure. Roughly half of the participants had active brown fat, and they were typically younger and had lower body mass index, body fat mass, and abdominal fat area than the participants with undetectable brown fat. While blood parameters were within the normal ranges for both groups, the brown fat-positive group had lower HbA1c (a measure of long-term blood glucose control), total cholesterol, and LDL-cholesterol compared to the brown fat-negative participants, even after adjusting the data for age, sex, and body fat composition.[57]

A retrospective study of more than 52,000 people who had cancer found that people with detectable brown fat had a lower prevalence of cardiometabolic diseases such as type 2 diabetes, coronary artery disease, congestive heart failure, and hypertension than those without detectable brown fat. The study revealed that nearly 10 percent of the participants had detectable brown fat. The prevalence of type 2 diabetes, coronary artery disease, hypertension, or congestive heart failure was lower in those with brown fat compared to those without. Although the researchers adjusted the analysis to accommodate the potential influence of cancer and various treatment characteristics, these data were obtained from a population of people with cancer who may already have metabolic alterations due to the disease. Nevertheless, the study implicates brown fat in supporting cardiometabolic health.[58]

Future research in nonshivering thermogenesis, mainly brown fat biology, will likely uncover ways to maximize the thermogenic capacity of brown fat to reach clinically significant improvements in metabolic health.

Immune function

Cold exposure may boost certain populations of immune cells. When healthy young men were exposed to cold multiple times over a period of six weeks, their CD25 lymphocytes increased after three weeks, while CD14 monocytes increased after six weeks. Other types of immune cells, such as leukocytes and neutrophils, did not change.[59]

Another study demonstrated that cold exposure increased numbers of white blood cells, including cytotoxic T lymphocytes, a specialized type of immune cell that can kill cancer cells. The white cell counts remained elevated at two hours of cold exposure. The participants' natural killer cells (white blood cells of the innate immune system) also increased.[60] A separate study noted similar findings.[61]

A study comparing regular winter swimmers who practiced more than once per week to non-habitual swimmers showed that resting concentrations of some white blood cells such as leukocytes and monocytes were higher compared to the non-habitual swimmers.[62] Additionally, a study found regular winter swimming may decrease respiratory tract infections by 40 percent.[63] These studies bolster anecdotal claims shared among communities of winter swimmers that they experience fewer colds and influenza.

While these studies indicate that cold exposure can boost some immune cells in younger people, future studies are needed to determine the effects in older people and whether the increase in immune cell number is associated with improved health.

Antioxidant enzyme activation

A normal byproduct of energy metabolism and exercise is the production of reactive oxygen species. Excess concentrations of reactive oxygen species can promote muscle damage, fatigue, immune dysfunction, DNA damage, and cellular senescence. Cold exposure appears to activate endogenous antioxidant enzymes by functioning as a hormetic stressor.

When healthy young men underwent 20 three-minute cryotherapy sessions, red blood cell concentrations of the antioxidant enzyme glutathione roughly doubled after ten sessions of cryotherapy but decreased slightly below baseline by the final session. Another antioxidant enzyme, superoxide dismutase, increased by approximately 43 percent compared to baseline by the final session.[64] Similarly, a study in healthy men found that a single three-minute whole-body cryotherapy increased superoxide dismutase activity by 36 percent and glutathione peroxidase activity by 68 percent, compared to levels three days before the cryotherapy session.[65]

Additional research may reveal whether the increase in antioxidant enzymes upon cold exposure has any effect on protecting against DNA damage, cellular senescence, or immune dysfunction.

Inflammation

Chronic inflammation is a key driver of the aging process and is associated with many age-related diseases, including arthritis.[66] Inflammation also occurs after periods of exercise. Research indicates that cold exposure may decrease inflammation in people with inflammatory conditions and in those who have undergone exercise training.[65][67]

Arthritis

Arthritis is an inflammatory degenerative joint disorder that can cause pain and reduced mobility.[68] Destruction of cartilage within the joints can drive arthritis. There is currently no cure for arthritis, but some treatments include pain relievers, anti-inflammatory drugs, exercise, and joint surgery.[69] Cold exposure may be an effective treatment to reduce inflammation and pain associated with arthritis.

Cold exposure may decrease pain in people with rheumatoid arthritis by decreasing inflammatory signaling molecules. In healthy people, five days of cold exposure decreased the pro-inflammatory protein IL-2 and the inflammatory E2 series of prostaglandins while increasing the anti-inflammatory protein IL-10.[69]

A study involving people with rheumatoid arthritis compared the effects of multiple sessions of different cold therapy modalities, including localized cryotherapy, whole-body cryotherapy at -76ºF (-60ºC), or whole-body cryotherapy at -166ºF (-110ºC). All of the participants received individual physical therapy or engaged in low-impact group exercise. Pain, assessed using a visual analog score, decreased in all treatment groups. Compared to baseline, the pain score decreased by 11 points with local cryotherapy, three points with whole-body cryotherapy at -76ºF (-60ºC), and 24 points with whole-body cryotherapy at -166ºF (110ºC).[70]

A separate study compared whole-body cryotherapy to traditional rehabilitation in postmenopausal women. Roughly half of the women received whole-body cryotherapy, and the remainder underwent a traditional rehabilitation program. After the treatments, both groups exhibited similar improvements in pain and disease activity, fatigue, time of walking, and the number of steps over a distance of 50 meters.[71] The pro-inflammatory molecules IL-6 and TNF-α decreased in both groups.

Some of the pain-alleviating effects of cold exposure, particularly in whole-body cryotherapy, may also be due to increased norepinephrine since inflammation itself causes pain. In fact, spinal injection of compounds that induce a release of norepinephrine alleviates pain in human and animal studies.[72][73]

Exercise-associated inflammation

A study in male athletes found that whole-body cryotherapy altered immunological parameters such as muscle enzymes and cytokine levels. The men maintained their regular training regimen, which involved both resistance and aerobic exercise, and underwent two-minute cryotherapy sessions once daily for five days. Compared to baseline, the men's circulating C-reactive protein (a marker of inflammation) concentrations remained stable, but IL-10, an anti-inflammatory cytokine, increased, and the pro-inflammatory cytokines IL-2 and IL-8 decreased. In addition, creatine kinase and lactate dehydrogenase, which are markers of muscle damage, decreased.[74]

Elite marathon runners who underwent whole-body cryotherapy after a running session had lower C-reactive protein levels than runners who underwent passive recovery. The two modalities were completed immediately after the exercise and at 24, 48, 72, and 96 hours afterward. C-reactive protein peaked at 24 hours after running in both groups. However, compared to pre-exercise levels, C-reactive protein increased by 123 percent with whole-body-cryotherapy and 515 percent with passive recovery at 24 hours. At 72 hours post-exercise, the C-reactive protein levels returned to baseline levels with whole-body cryotherapy, but levels persisted with passive recovery. The pro-inflammatory mediator IL-1 beta and the anti-inflammatory mediator IL-10 peaked one hour post-exercise in both recovery groups. However, whole-body cryotherapy was associated with a greater decrease in IL-1 beta and a greater increase in IL-1ra, a cytokine inhibitor that reduces the pro-inflammatory response, one hour post-exercise compared to passive recovery.[75]

Elite tennis players who engaged in whole-body cryotherapy had decreases in the pro-inflammatory cytokine TNF-alpha and increases in IL-6, a cytokine that exhibits both pro- and anti-inflammatory properties and plays a role in muscle repair. These inflammatory alterations were associated with improvements in stroke effectiveness.[67]

It is important to note that these anti-inflammatory qualities of cold exposure on exercise and athletic performance, while probably beneficial in some contexts, may add some level of nuance or complexity to any discussion of the practice's effects.

Microbiome

The microbiome is composed of all of the microorganisms that reside both on and within the human body. Studies in mice suggest that cold exposure can alter the composition and activity of the gut microbiome to improve energy metabolism and support thermogenesis.

Upon cold exposure, the composition of gut microbiota in mice is altered to support the activation of nonshivering thermogenesis in part by increasing the uptake of carbohydrates and lipoprotein-derived triglycerides.[76][77][78] Conversely, mice lacking gut microbiota have impaired nonshivering thermogenesis and decreased insulin sensitivity.[79] Translational studies are needed to evaluate the impact of the gut microbiome on the activation of nonshivering thermogenesis in humans.

Brain effects of cold exposure

Cold exposure elicits the release of norepinephrine into the brain and may activate the cold shock protein RBM3. Some studies suggest that cold exposure may improve mood and cognition, decrease depression, and protect against neurodegenerative disease.

Mood and cognition

One of the most consistent and profound physiological responses to cold exposure is a robust release of norepinephrine into the bloodstream as well as in the locus coeruleus, the brain's main source of norepinephrine.[80][14] Norepinephrine is a key player in the mood and cognitive-enhancing effects of cold exposure. As described above, norepinephrine is a neurotransmitter involved in vigilance, focus, attention, and mood.[81] Generally, lower norepinephrine activity is associated with inattention, decreased focus and cognitive ability, low energy, and poor mood.[82][83] Pharmacological depletion of norepinephrine can lead to depression.[84] In fact, both ADHD and depression are sometimes treated with norepinephrine reuptake inhibitors, but these drugs carry some risks.[85]

After adults who had been diagnosed with depression underwent ten cryotherapy sessions, they showed marked reductions in their depressive symptoms and improved quality of life, mood, and disease acceptance, suggesting that whole-body cryotherapy is beneficial for mental well-being and quality of life.[86] In addition, some anecdotal evidence suggests that cold exposure improves mood and may help treat depression. Findings from a case report suggest that a 68ºF (20°C) cold shower for two to three minutes preceded by a gradual adaptation period can relieve depressive symptoms when performed once or twice daily over the course of several weeks to months.[87] A separate case report demonstrated that cold water swimming once or twice a week improved mood and reduced depressive symptoms in young women.[88] These reports are anecdotal and involve exercise as a confounding factor. However, studies in animals suggest a mechanism by which cold exposure may improve mood.

More direct evidence is needed to link cold exposure as a strategy for the potential treatment of cognitive and mood disorders, but it is an interesting and promising area of inquiry.

Brain aging

Nerve synapses facilitate neuronal communication and memory formation. Synapse loss occurs with normal brain aging and is accelerated in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease and after traumatic brain injury.[89][90][91] Hibernating animals also experience synapse loss during their period of hibernation, but synapse restoration occurs upon arousal. Studies in hibernating animals demonstrate that induction of cold shock proteins, particularly RBM3, is important for synaptic regeneration after hibernation.[92][93][94]

Interestingly, synaptic regeneration after cold exposure has also been observed in mice, which are not hibernating animals. Briefly cooling mice to a body temperature similar to that of some hibernating animals promoted synapse reassembly and temporarily increased RBM3 in the animals' brains. After repeated application of the procedure, RBM3 expression increased and persisted for several weeks. In the same study, mice predisposed to have Alzheimer’s disease lost the ability to upregulate RBM3 and subsequently lost the ability to reassemble synapses. The upregulation of RBM3 in the mice promoted sustained synaptic protection, prevented behavioral deficits and neuronal loss, and prolonged survival.[25][26]

An in vitro study using human astrocytes, a type of brain cell, found that decreasing the culturing temperature from 37°C (normal human body temperature) to 35°C activated RBM3.[95] The extent to which RBM3 protects against neurodegeneration in humans, however, is still not entirely understood.

It is plausible that therapeutic strategies that increase norepinephrine, such as cold-water immersion and whole-body cryotherapy, may lower inflammation and facilitate attenuation of what is otherwise a major contributor to the aging process in the brain. Additional studies are needed in humans to determine the degree to which RBM3 may be activated upon cold exposure and determine the potential for RBM3 to protect against neurodegeneration.

Cold exposure exerts variable effects with exercise

Cold exposure is widely utilized as a therapy to improve muscle recovery and increase performance. Numerous studies have investigated the effects of cold exposure after exercise or athletic competition, with mixed results. The inconsistent findings in these studies are likely due to the nature of the exercise (endurance versus resistance) and the time of the cold exposure with respect to exercise (pre-exercise, immediately after exercise, or later). Studies suggest that cold exposure immediately after resistance training may blunt muscle adaptations, while cold exposure after endurance exercises such as cycling or long-distance running may improve muscle recovery and performance.

Timing influences the effects of cold exposure with exercise

Immediately after exercise, blood concentrations of pro-inflammatory proteins and reactive oxygen species increase.[96] Conversely, concentrations of anti-inflammatory proteins peak within the first hour post-exercise, likely to restrict the magnitude and duration of the preceding inflammatory response.[97] These physiological responses play roles in mediating beneficial adaptations to exercise.[98] However, excessive exercise-induced inflammation can promote muscle damage, fatigue, and immune dysfunction, the extent of which varies according to the duration and intensity of exercise.[99]

Cold exposure immediately after exercise may diminish the beneficial training adaptations by blunting the immune response. A study in young elite athletes evaluated the effect of ice pack application after sprint interval training. After the athletes exercised, they applied ice packs to their hamstring muscles for two sessions lasting 15 minutes with a 15-minute rest between each session. The athletes' blood concentrations of anabolic hormones (associated with repair and synthesis) increased immediately after exercise, but after ice pack application the hormones decreased and the catabolic hormone (associated with breakdown) IGFBP-1 increased, compared to recovery without cold exposure.[100]

Use of cryotherapy, cold-water immersion, or ice packs immediately after training may undermine certain beneficial effects of having acute periods of low-grade inflammation. The peak anti-inflammatory response appears to occur up to one hour after activity, and some inflammation and immune activation before that point may be beneficial.

Cold exposure may diminish the effects of resistance exercise

The type of activity one engages in also influences the outcome of cold exposure on athletic performance and recovery. Resistance training, also referred to as strength or weight training, notably increases strength and skeletal muscle mass, but some studies indicate that cold exposure immediately after training can blunt these adaptations.

One study compared the effects of cold water immersion to active recovery and found that cold water immersion after resistance training attenuated long-term gains in muscle mass and strength in physically active men. Half of the men underwent cold water immersion, while the others completed active recovery within five minutes of completing a training session. Both groups of men saw an increase in muscle mass, but the active recovery group gained more muscle mass than the cold-water immersion group, suggesting that cold water immersion partially blunted muscle hypertrophy. Additionally, the type II muscle fibers (required for very short-duration, high-intensity bursts of power) increased in the active recovery group but not in the cold water immersion group. Biomarkers that are usually associated with hypertrophy (muscle growth), including the activation of satellite cells and mTOR signaling (a regulator of growth), decreased in the cold exposed group.[101]

Additionally, studies suggest that cold water immersion after resistance exercise may interfere with regenerative processes and blunt muscle performance.[102][103] These detrimental effects may be in part due to alterations in protein synthesis via suppression of ribosomal biogenesis. Ribosomes are cellular machinery that translate genetic information into protein. When healthy athletes underwent brief cold water immersion sessions, their upstream signaling and activation of ribosomal biogenesis decreased, suggesting that cold water immersion immediately after resistance training may blunt protein synthesis and muscle mass gain.[104]

Delaying cold water immersion by at least one hour after resistance exercise may improve recovery, however. When healthy young men underwent whole-body cryotherapy one hour after plyometric exercise (squat jumps and leg curls), their performance measures improved up to 72 hours after the treatment. The men's perceived pain sensation at rest and during squat decreased with cryotherapy, and their knee torque development (a measure of force produced) was greater.[105] This study only utilized one training session, so additional studies investigating the long-term effects of cold exposure after frequent exercise may help determine whether delayed cold exposure after resistance training is beneficial.

While these studies suggest that cold exposure immediately after resistance training can blunt muscle adaptations, many studies have found cold exposure (both cold water immersion and whole-body cryotherapy) has no detrimental effects on muscle strength, endurance, or mass.[106][107][108][109][110][111] The conflicting results could be due to a variety of factors, including type of cold exposure (ice pack versus cold water immersion versus whole-body cryotherapy), duration of cold exposure, or the type and duration of resistance training. For now, it seems prudent in the context of strength training to exercise caution in the timing of cold exposure immediately after exercise.

Cold exposure and endurance exercise

Cold exposure generally elicits positive effects in the setting of endurance exercise. This may be due to the fact that the adaptations that occur are more specific to endurance activities or due to the timing that the cold exposure was done post-exercise.

A meta-analysis of nine randomized controlled trials found that cold water immersion improved muscle soreness to a greater extent compared to passive recovery. The studies included in the analysis utilized cold water immersion within one hour of the end of exercise in a water bath at temperatures of 41° to 59°F (5° to 15°C) for anywhere between 5 and 20 minutes. They involved a single session of exercise, including running, cycling, or jumping, and included only one cold water immersion after the exercise session. The immersion in cold water ranged from lower limbs to immersion of the whole body, excluding the head and neck. The results of each study were pooled, and the mean difference between cold water immersion compared to passive recovery favored cold water immersion for an improvement in muscle recovery. When subgroups were analyzed, the mean difference in reduced muscle soreness in studies using water temperatures between 34° and 59°F (11° and 15°C) was approximately 50 percent greater than studies using temperatures between 41° and 50°F (5° to 10°C).[112]

Another meta-analysis evaluated the effects of cold water immersion for the recovery from team sports-related activities such as soccer or volleyball. The analysis pooled data from 23 studies comprising 606 participants and determined the mean difference of neuromuscular performance (jump performance and sprint times), subjective measures of fatigue, muscle soreness, and biochemical markers, following either cold water immersion or passive recovery performed no less than 24-hours post-exercise stressor. Passive recovery primarily included seated rest. A majority of the studies evaluated the effects of cold water immersion 24 hours following an exercise stressor, while six studies extended the research to 72 and 90 hours following an exercise stressor. The temperatures for cold water immersion ranged between 41° and 59°F (5° and 15°C), with most studies applying cold water between 50° and 54°F (10° and 12°C). Cold-water immersion lasted anywhere between one and 15 minutes, with shorter immersion times typically repeated three to five times.

Neuromuscular recovery improved with cold water immersion compared to passive recovery when performed 24 hours following the exercise stressor. However, cold water immersion had minimal effects on enhanced recovery one hour, 48 hours, and beyond 90 hours following the exercise stressor. Cold-water immersion improved the perception of fatigue, defined as a reduction in physical or functional performance, 72 hours following the exercise stressor compared to those in passive recovery. Cold-water immersion did not enhance the perception of fatigue at any other time points. Muscle soreness and clearance of creatine kinase (a marker of muscle damage) were not altered with cold water immersion. The reviewers concluded that cold water immersion can attenuate decrements in neuromuscular performance 24 hours following team sports, but studies evaluating recovery beyond 48 hours are needed to determine whether the perceived recovery leads to enhanced performance in games or training.[113]

Cold exposure may be especially beneficial in the context of running to accelerate recovery and reduce soreness.[114][115][116] Cold exposure may mitigate high levels of pro-inflammatory proteins post-exercise, which can cause acute performance deterioration and muscle damage. This can be problematic for training even several days later since there may be a greater risk of injury due to residual soreness and changes in muscle function. For example, a study of 11 runners who regularly participated in marathons found that whole-body cryotherapy decreased the inflammatory response that coincides with enhanced muscle recovery. The men completed an approximately 45-minute treadmill run once a month, followed by either a passive recovery or whole-body cryotherapy. The recovery modalities were completed immediately after the race and again at 24, 48, 72, and 96 hours after. The runners' C-reactive protein (a biomarker of inflammation) peaked at 24 hours after running in both groups. However, compared to pre-exercise levels, C-reactive protein increased by 123 percent with whole-body cryotherapy and 515 percent with passive recovery at 24 hours. At 72 hours post-exercise, the C-reactive protein levels returned to baseline levels with whole-body cryotherapy but levels persisted with passive recovery. No difference was observed in the inflammatory cytokine TNF-alpha. Additionally, the cytokines IL-6 and IL-10 increased immediately after exercise regardless of the recovery modality with no observed differences in response between groups. Whole-body cryotherapy was associated with a greater decrease in the pro-inflammatory cytokine IL-1 beta and a greater increase in the anti-inflammatory cytokine IL-1ra one hour post-exercise compared to passive recovery.[75]

Whole-body cryotherapy may also alter the inflammatory process in endurance athletes involved in other sports such as tennis and rowing.[65][67] Elite tennis players who engaged in whole-body cryotherapy experienced reduced levels of the pro-inflammatory cytokine TNF-alpha and increased IL-6, a cytokine with both pro- and anti-inflammatory properties that plays a role in muscle repair. These inflammatory alterations were associated with improvements in stroke effectiveness.[67]

The performance enhancements that endurance athletes experience from post-exercise cold exposure may even be sustained over a prolonged time period. A study in elite cyclists who engaged in frequent cold water immersion sessions over a 39-day training period demonstrated improvements in performance. The cyclists experienced a 4.4 percent increase in average sprint power, a 3 percent enhancement in repeat cycling performance, and a 2.7 percent increase in power over the 39-day training period. While these improvements seem minimal, they may be substantial for elite athletes.[117]

Cold exposure safety concerns

As described above, cold exposure poses some health risks, especially in unsupervised or uncontrolled conditions. The most common risk associated with cold exposure is hypothermia, a condition in which a person's core body temperature drops below 95°F (35°C).[118] Symptoms of hypothermia include rapid breathing, shivering, pale skin, confusion, and drowsiness.[118] If hypothermia occurs in a large body of water such as a lake or ocean, it can impair respiration and may lead to drowning.

Other risks of cold exposure include afterdrop and frostbite. Afterdrop refers to a drop in core body temperature after exiting cold water and is common among open-water swimmers. Immediately after exiting cold water, the cooler blood from peripheral tissue returns to the central circulation, inducing a drop in core body temperature and subsequent hypothermia[119] Frostbite occurs when the skin freezes. It is common on peripheral tissues such as the fingers, toes, nose, ears, cheeks, and chin.[120] Exposing skin to air temperatures less than 10°F (-12.2°C) can cause frostbite. As a result, a person can develop frostbite in 30 minutes or less when the wind chill is -15°F (-26°C) or lower.[121] While whole-body cryotherapy involves standing in temperatures as low as -289˚F (-178˚C), sessions typically last only a few minutes and users are instructed to wear socks, gloves, and a hat to minimize the possibility of developing frostbite.

Cold exposure is contraindicated in the setting of alcohol consumption and hypothyroidism, due to their capacity to decrease cold tolerance and increase the likelihood of adverse events.[122][123][124][125] Caution should be exercised when alternating from hot to cold exposure (a common practice among sauna users), as dramatic changes in blood pressure could occur.[126]

Conclusion

A growing body of evidence demonstrates that cold exposure may serve as a hormetic stressor that switches on a host of protective mechanisms that reduce inflammation, activate antioxidant enzymes, improve athletic performance and promote recovery, and boost the immune system to protect against age-related diseases. Post-exercise cold water immersion may also increase PGC-1 alpha, a protein that promotes mitochondrial biogenesis. Cold exposure activates brown fat, a type of adipose tissue that is associated with a lower prevalence of cardiometabolic diseases and may be a promising therapy for obesity and obesity-related disorders. Early studies in mice suggest that cold exposure can alter the composition and activity of the gut microbiome to improve energy metabolism and support thermogenesis. While more direct evidence is needed, cold exposure may even serve as a strategy for the treatment of cognitive and mood disorders. Although cold exposure for the purposes of health is an ancient practice, it remains a promising beneficial lifestyle behavior that should be conducted with caution and supervision.

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Edited by Gordo
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Personally I have always experienced a significant improvement in mood when swimming in water that shocks you a good bit when you first immerse yourself. Like an unseated pool or ocean water. I noticed this many years ago long before I had any concept that it would do that so it certainly wasn’t a placebo effect.

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This new study [1] found that the production of FGF-21 is necessary for the metabolic and longevity benefits of protein restriction (PR) in mice. Specifically, in mice who were genetically altered to not produce FGF-21, PR didn't extended lifespan like it normally does.

In fact, as can be seen in the graph on the right, protein-restricted FGF-21 knockout mice (Fgf21 KO-LP) died sooner (and were more frail in a graph not shown) than knockout mice fed a normal amount of protein. This is the opposite of the relationship in the wild-type (WT) mice in the left graph with normal FGF-21 levels, where protein-restricted mice lived longer. It is also worth noting that just like in virtually every other rodent longevity experiment, the mice in this study were all subjected to mild cold exposure, being housed at normal room temperature (23C) which well below their thermoneutral temperature.

Screenshot_20220424-162120_Chrome.jpg

 

This would seem to support the hypothesis that cold exposure (which boosts FGF-21) and dietary restriction may act synergistically to increase healthspan and lifespan.

--Dean

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[1] Hill, C.M., Albarado, D.C., Coco, L.G. et al. FGF21 is required for protein restriction to extend lifespan and improve metabolic health in male mice. Nat Commun 13, 1897 (2022). https://doi.org/10.1038/s41467-022-29499-8

Dietary protein restriction is increasingly recognized as a unique approach to improve metabolic health, and there is increasing interest in the mechanisms underlying this beneficial effect. Recent work indicates that the hormone FGF21 mediates the metabolic effects of protein restriction in young mice. Here we demonstrate that protein restriction increases lifespan, reduces frailty, lowers body weight and adiposity, improves physical performance, improves glucose tolerance, and alters various metabolic markers within the serum, liver, and adipose tissue of wildtype male mice. Conversely, mice lacking FGF21 fail to exhibit metabolic responses to protein restriction in early life, and in later life exhibit early onset of age-related weight loss, reduced physical performance, increased frailty, and reduced lifespan. These data demonstrate that protein restriction in aging male mice exerts marked beneficial effects on lifespan and metabolic health and that a single metabolic hormone, FGF21, is essential for the anti-aging effect of this dietary intervention.

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  • 4 weeks later...
  • 2 months later...

Interesting.  My take:

(1) Reducing availability of glucose to tumor cells slows their growth.

(2) Brown adipose tissue competes with tumor cells for glucose absorption.

(3) Cold temperatures convert some white fat into brown fat.

Notes:

(1) Dean has brought (2) and (3) to our attention previously.

(2) Calorie Restriction, of course, reduces serum glucose quite a bit.

  --  Saul

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