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Thanks for the reminder and the link mccoy. A search on that articles pmid found three posts where we discussed that article in the context of immune system boosting by cold exposure : https://www.crsociety.org/search/?&q=10444630&search_and_or=or That's why it's good to include the pmid of studies under discussion. --Dean
Cold Exposure & Exercise Boost Immune System Function and Slows Cancer I've got two big posts for this thread in the pipeline (on Ikeno et al and on Speakman's body of work). But I had to put those on hold to report on this new study , hot off the presses (popular press account). In fact, it's very related to several ongoing threads on these forums, so I think I'll be making several other posts as well to point to this one. It relates to four topics near and dear to our hearts, and germane to this thread - exercise, immune system function, cancer and cold exposure. Unlike a lot of the studies we discuss, with many moving parts, this one was relatively straightforward, at least in its results. Researchers divided mice into individual cages, some with running wheels and some without. Unfortunately, they don't report the housing temperature, except to say (in the supplemental material) the mice were housed in a "thermo-stated environment", which I interpret to mean a temperature-controlled room. Since they didn't mention temperature explicitly, it seems almost certain the housing temperature was around 'normal laboratory conditions', i.e. 21-22 °C, which as we know is pretty chilly for mice - more on that below. The mice were allowed to run voluntarily (or not for the control mice) for four weeks. Then the mice were injected with various cancer promoting agents to induce cancer. After the injection, a group of the initially-sedentary mice were given a running wheel, to see how starting exercise after cancer initiation would impact the outcome. All the mice were then monitored to see how their tumor burden and blood chemistry changed over time. What they found was quite dramatic. Giving mice free access to a running wheel reduced tumor burden by about 60% in both sexes, across range of ages (young, adult, older), and across a variety of different types of cancers, including lung cancer, liver cancer and skin cancer. But only if exercise was performed prior to cancer initiation - picking up the exercise habit after cancer had started didn't help slow tumor growth. And this effect wasn't a result of reduced food intake or weight loss in the exercisers (i.e. crypto-CR). The both sedentary and running mice we given ad lib access to food, and the running mice ate enough to compensate for the calories spent exercising, and so didn't lose weight. In fact, they ended up avoiding the weight loss exhibited by the cancer-ridden sedentary mice, and so weighed slightly more than the sedentary controls by the end of the study. In short, the mice with access to the running wheel ate more, burned it off with lots of exercise (see below for just how much) so weighed virtually the same, and enjoyed dramatically slower cancer growth and tumor burden than sedentary control mice. Just to be graphic and to show how dramatic the effect was, check out these representative pictures of lung tumors taken from mice in the sedentary (CON - left) and exercise (EX - right) groups (note: the ugly black stuff is the tumor tissue): So just how much were the mice running? It turns out the answer is a heck of a lot. The male mice in this study ran four miles (6.8 km) per day on the voluntary running wheel. That is virtually an identical distance to the male mice of the same strain in this study  (which found exercise increases the growth of new neurons - another great benefit!), which in addition to distance also reported how many minutes per day the mice ran. It turns out that to log 4 miles per day, the mice spend about 550 minutes per day chugging away on the running wheel. That's over 9 hours the mice spent exercising, and is coincidentally almost exactly how much I exercise per day, mostly spent gently pedalling away at my bike desk, which now that I think about it seems quite analogous to a mouse on a running wheel. It's neat when things work out like that☺. So what was the mechanism by which cancer was so improved in these chilly little exercise fanatics? That's where things get even more interesting. Through a series of experiments, the researchers determined it was the result of an exercise-induced increase in both epinephrine and Interleukin-6 (IL-6), which in turn boosted the immune systems (specifically, natural killer or NK immune cells) of the running mice so as to attack the cancer. This is a cool discover for several reasons. First, the obvious one - it's good to slow the growth of cancer! But also, one concern we've been discussing a lot around here lately (e.g. here and here) is the potential negative impact of CR on immunity, and in particular our ability to fight off infections / invaders after they've gotten a foothold in our bodies. That is exactly the problem this study addresses and appears to provide an answer for. Namely, lots of low-intensity exercise coupled with mild cold exposure appears to dramatically improve the immune system's ability to tag and fight off foreign invaders - in this case cancer cells. OK you might be saying - maybe I'll buy that nearly continuous, low-intensity exercise is great for boosting important immune system cell types, preventing/slowing cancer and (as a bonus) promoting neurogenesis (e.g. ). But besides your inference that the mice in this study were housed at normal lab temperatures and therefore were thermally stressed on top of the exercise, what's the link to cold exposure? First off - as we've seen several times in this thread, in studies like Koizumi & Walford (PMID 9032756), and Ikeno et al. (PMID 16424282 - my post about which is in the works, stay tuned...) , mice housed in cool conditions exhibit dramatically less cancer mortality than mice housed at thermoneutrality - i.e. the temperature they are comfortable at. So it's very likely the tumor burden would have been even worse in the sedentary and in the exercising mice if they'd been house in warm conditions rather than the "normal" lab temperature presumably employed in this study. But what's most relevant and exciting about these results vis a vis cold exposure are the details of the mechanism - i.e. elevated epinephrine and IL-6. Anyone who has been paying attention will know that cold exposure elevates epinephrine. In fact, epinephrine is the primary signalling molecule the body uses to orchestrate its response to cold exposure. I strongly suspect an increase in circulating epinephrine is the likely cause of the increase in resting heart rate (43 → 52 BMP) I've noticed since starting serious cold exposure. As for interleukin-6, it's funny, in the post where I discuss CE's impact on the immune system, I noticed that PMID: 25338085 found humans who exercised at 0°C exhibited a reduction in a bunch of inflammatory markers, including "Interleukin-2, IL-5, IL-7, IL-10, IL-17, IFN-γ, Rantes, Eotaxin, IP-10, MIP-1β, MCP-1, VEGF, PDGF, and G-CSF", relative to people who exercised at normal room temperature (22 °C). At the time I thought it strange that one of the few interleukins I'd heard of (IL-6) wasn't on the list. It turns out IL-6 is often one of the 'good guys', particularly for muscles, unlike many of the other interleukins, which are pro-inflammatory and implicated in a number of diseases of aging, particularly when chronically elevated. In fact, IL-6 isn't just left unchanged by cold exposure - it is increased in both rats  and humans. Regarding humans, from that same post, PMID 8925815 found IL-6 was increased (along with bunch of immune system cell types - see the post for the list) in humans as a result of chronic (6 weeks) of cold exposure, and PMID 10444630 found cold exposure after exercise boosts IL-6 levels in humans as well. This study I just uncovered , found the same thing - cold exposure after exercise increased (+30%) the already elevated level of IL-6 that resulted from exercise, as opposed to IL-6 dropping precipitously (-69%) when subjects were exposed to warm conditions after exercise. Here is the dramatic graph from  showing the post-exercise IL-6 levels in cold and warm subjects during the 90-minutes after exercise: What's really interesting is the new light these results shed on the mechanism by which cold exposure reduces cancer. Previously I thought (and perhaps Michael did as well) that CE reduced cancer mortality simply by reducing body temperature like CR does, which in turned simply reduced cellular proliferation rate and therefore cancer progression. Sort of like how plants grow more slowly in cold weather - metabolic processes, including cancer growth, just slow down when it's cold. But these results suggest that reduced cancer mortality as a result of CE and/or exercise is likely a result of active upregulation of immune system function, in particularly increased natural killer (NK) cells, triggered by elevated epinephrine and IL-6. In short, this appears to be yet another pathway by which CE can improve health & longevity, both independently and synergistically with exercise. And I can't help but note for Michael's benefit that this beneficial CE pathway is quite independent of "obesity-avoidance". So what have we learned from all this? I'm tempted to summarize it as "Dean was right"☺. But let me be a little more explicit. The evidence suggests that exercise coupled with cold exposure, or cold exposure alone, can reduce cancer growth and boost important aspects of immune system function (e.g. natural killer or NK cells) by increasing circulating levels of norepinephrine and interleukin-6. This finding is particularly interesting and relevant given concerns about CR's potential deleterious effects on immunocompetence, and the new human CR study Michael announced a short time ago to investigate the effects of CR on the immune system. I hope I'm not disqualified from participating in the new study as a result of my dietary intake, parts of which Michael characterizes as "stupid high". I'd really like to see how my immune system compares with other CRers. --Dean ----------  Cell Metab. 2016 Mar 8;23(3):554-62. doi: 10.1016/j.cmet.2016.01.011. Epub 2016 Feb 16. Voluntary Running Suppresses Tumor Growth through Epinephrine- and IL-6-Dependent NK Cell Mobilization and Redistribution. Pedersen L(1), Idorn M(2), Olofsson GH(2), Lauenborg B(1), Nookaew I(3), Hansen RH(4), Johannesen HH(4), Becker JC(5), Pedersen KS(1), Dethlefsen C(1), Nielsen J(6), Gehl J(7), Pedersen BK(1), Thor Straten P(8), Hojman P(9). Full text: https://sci-hub.io/10.1016/j.cmet.2016.01.011 Regular exercise reduces the risk of cancer and disease recurrence. Yet the mechanisms behind this protection remain to be elucidated. In this study, tumor-bearing mice randomized to voluntary wheel running showed over 60% reduction in tumor incidence and growth across five different tumor models. Microarray analysis revealed training-induced upregulation of pathways associated with immune function. NK cell infiltration was significantly increased in tumors from running mice, whereas depletion of NK cells enhanced tumor growth and blunted the beneficial effects of exercise. Mechanistic analyses showed that NK cells were mobilized by epinephrine, and blockade of β-adrenergic signaling blunted training-dependent tumor inhibition. Moreover, epinephrine induced a selective mobilization of IL-6-sensitive NK cells, and IL-6-blocking antibodies blunted training-induced tumor suppression, intratumoral NK cell infiltration, and NK cell activation. Together, these results link exercise, epinephrine, and IL-6 to NK cell mobilization and redistribution, and ultimately to control of tumor growth. Copyright © 2016 Elsevier Inc. All rights reserved. PMID: 26895752 ------------  BMC Neurosci. 2012 Jun 8;13:61. doi: 10.1186/1471-2202-13-61. Voluntary wheel running in mice increases the rate of neurogenesis without affecting anxiety-related behaviour in single tests. Garrett L(1), Lie DC, Hrabé de Angelis M, Wurst W, Hölter SM. Author information: (1)Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg/Munich, Germany. Free full text: http://bmcneurosci.biomedcentral.com/articles/10.1186/1471-2202-13-61 BACKGROUND: The role played by adult neurogenesis in anxiety is not clear. A recent study revealed a surprising positive correlation between increased anxiety and elevated neurogenesis following chronic voluntary wheel running and multiple behavioural testing in mice, suggesting that adult hippocampal neurogenesis is involved in the genesis of anxiety. To exclude the possible confounding effect of multiple testing that may have occurred in the aforementioned study, we assessed (1) the effects of mouse voluntary wheel running (14 vs. 28 days) on anxiety in just one behavioural test; the open field, and (2), using different markers, proliferation, differentiation, survival and maturation of newly born neurons in the dentate gyrus immediately afterwards. Effects of wheel running on anxiety-related behaviour were confirmed in a separate batch of animals tested in another test of anxiety, the light/dark box test. RESULTS: Running altered measures of locomotion and exploration, but not anxiety-related behaviour in either test. 14 days running significantly increased proliferation, and differentiation and survival were increased after both running durations. 28 day running mice also exhibited an increased rate of maturation. Furthermore, there was a significant positive correlation between the amount of proliferation, but not maturation, and anxiety measures in the open field of the 28 day running mice. CONCLUSIONS: Overall, this evidence suggests that without repeated testing, newly born mature neurons may not be involved in the genesis of anxiety per se. PMCID: PMC3504529 PMID: 22682077 -------------  J Athl Train. 2012 Nov-Dec;47(6):655-63. doi: 10.4085/1062-6050-47.5.09. Interleukin-6 responses to water immersion therapy after acute exercise heat stress: a pilot investigation. Lee EC(1), Watson G, Casa D, Armstrong LE, Kraemer W, Vingren JL, Spiering BA, Maresh CM. Author information: (1)Department of Kinesiology, University of Connecticut, 2095 Hillside Road, U-1110, Storrs, CT 06269-1110, USA. firstname.lastname@example.org Free full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3499890/ CONTEXT: Cold-water immersion is the criterion standard for treatment of exertional heat illness. Cryotherapy and water immersion also have been explored as ergogenic or recovery aids. The kinetics of inflammatory markers, such as interleukin-6 (IL-6), during cold-water immersion have not been characterized. OBJECTIVE: To characterize serum IL-6 responses to water immersion at 2 temperatures and, therefore, to initiate further research into the multidimensional benefits of immersion and the evidence-based selection of specific, optimal immersion conditions by athletic trainers. DESIGN: Controlled laboratory study. SETTING: Human performance laboratory Patients or Other Participants: Eight college-aged men (age = 22 ± 3 years, height = 1.76 ± 0.08 m, mass = 77.14 ± 9.77 kg, body fat = 10% ± 3%, and maximal oxygen consumption = 50.48 ± 4.75 mL·kg(-1) min(-1)). MAIN OUTCOME MEASURES: Participants were assigned randomly to receive either cold (11.70°C ± 2.02°C, n = 4) or warm (23.50°C ± 1.00°C, n = 4) water-bath conditions after exercise in the heat (temperature = 37°C, relative humidity = 52%) for 90 minutes or until volitional cessation. RESULTS: Whole-body cooling rates were greater in the cold water-bath condition for the first 6 minutes of water immersion, but during the 90-minute, postexercise recovery, participants in the warm and cold water-bath conditions experienced similar overall whole-body cooling. Heart rate responses were similar for both groups. Participants in the cold water-bath condition experienced an overall slight increase (30.54% ± 77.37%) in IL-6 concentration, and participants in the warm water-bath condition experienced an overall decrease (-69.76% ± 15.23%). CONCLUSIONS: We have provided seed evidence that cold-water immersion is related to subtle IL-6 increases from postexercise values and that warmer water-bath temperatures might dampen this increase. Further research will elucidate any anti-inflammatory benefit associated with water-immersion treatment and possible multidimensional uses of cooling therapies. PMCID: PMC3499890 PMID: 23182014 --------  Clin Exp Immunol. 2010 Jul 1;161(1):171-5. doi: 10.1111/j.1365-2249.2010.04156.x. Epub 2010 Apr 29. The effect of adrenomedullin and cold stress on interleukin-6 levels in some rat tissues. Yildirim NC(1), Yurekli M. Author information: (1)Tunceli University, Faculty of Engineering, Department of Environmental Engineering, Tunceli, Turkey. email@example.com Free full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2940162/ Stress known to stimulate sympathetic activity, as well as the hypothalamic-pituitary-adrenal axis (HPA), produces a significant increase in adrenomedullin (AdM) levels, suggesting a regulatory or protective role for AdM in countering HPA activation that follows a variety of stressors. Stressors can modulate the secretion of proinflammatory cytokines. Interleukin (IL)-6 is a potent activator of the HPA and appears to play a pathogenic role in conditions related to stress. In the present study, we investigated the administration of AdM on IL-6 levels in cold exposed rats. Male Wistar rats were divided into four groups as control, adrenomedullin treatment, cold stress and cold stress+adrenomedullin-treated groups. In the adrenomedullin-treated group, animals received intraperitoneal (i.p.) injection of adrenomedullin (2000 ng/kg body weight) once a day for a week. For the cold stress exposure the rats were kept in separate cages at 10 degrees C for a week. Control group rats were kept in laboratory conditions. The concentration of IL-6 was determined using an enzyme-linked immunosorbent assay (ELISA) kit. When compared to control, IL-6 levels increased significantly in the cold stress- and adrenomedullin-treated groups (P<0.05). Administration of AdM in addition to cold stress decreased IL-6 levels in lung and liver, but increased in brain and heart when compared to control (P<0.05). The results suggest that cold stress may induce increase of rat proinflammatory cytokine IL-6 and adrenomedullin may play a regulatory or protective role for cold stress. PMCID: PMC2940162 PMID: 20456410
Olive Oil Increases Uncoupling Protein Gene Expression in BAT & Skeletal Muscles Here is an interesting one to tide people over while I finish up a big post on Speakman's work on cold exposure, BAT, metabolic rate & longevity. In this study , researchers fed rats ad lib diets high in fat - 40% of calories, which not far from typical human consumption. They divided the rats into four groups, feeding them four different fats - olive oil (OO - MUFA-rich), sunflower oil (SO - PUFA-rich), palm oil (PO - SFA-rich), and beef tallow (BT - SFA-rich). No mention is made of the OO being "extra virgin", and it came from one of Spain's biggest olive oil companies (Koipe SA) so I think it's probably safe to assume it was run-of-the-mill olive oil rather than high-polyphenol EVOO. All the mice were housed at "normal" lab temperature (22 °C) for the duration of the experiment, which is chilly for rats. After four weeks on each of the diets, all four groups had gained about the same amount of weight - about 50% of their initial body weight! Weight of BAT tissue wasn't significantly different between the groups. What was interesting was the amount of gene expression of the three important uncoupling proteins, UCP-1, UCP-2 and UCP-3 in various tissues, including brown adipose tissue (BAT), white adipose tissue (WAT) and skeletal muscles. Here are graphs comparing UCP expression in BAT and muscle tissue for the four diets: The letters (a, b) above the bars represent which groups were significantly different As you can see, olive oil significantly boosted UCP1, UCP2, and UCP3 messenger RNA expression in BAT, and UCP3 mRNA expression in muscle tissue relative to the other three fat sources. In terms of actual UCP content in the various tissues on the various diets (as opposed to just messenger RNA expression shown above), only UCP2 was higher in BAT and UPC3 was higher in muscle tissue in the OO group relative to the other diets, particularly the SFA-rich diets: As we'll see in my next post, both UCP2 and UCP3 are associated with increased longevity, so it is interesting to see them elevated in BAT and muscle tissue by OO. Finally, while the OO diet increased total body oxygen consumption per gram of body weight (i.e. metabolic rate) relative to the other diets, oxygen consumption by BAT wasn't any different between groups. I suspect the rats weren't cold-stressed enough for BAT to majorly kick in, since they were feeding ad lib and gained over 50% of their initial body weight during the four weeks of the study (240g → ~370g), presumably mostly as highly insulating white fat. The authors checked for a bunch of different possible causes for why OO might boost UCP gene expression including differential changes to circulating hormones, glucocorticoids, or insulin. Nope - none of them were significantly different across the diets. They suggest instead that it may be the oleic acid in OO being incorporated into cell membranes and increasing the responsiveness of cells to UPC-stimulating adrenaline: The explanation of the effects of olive oil is not clear. It seems that these effects are not mediated by systemic metabolic changes, but rather may be related to a local effect produced by oleic acid on IBAT and gastrocnemius muscle. In our laboratory, we observed that, after a 4-wk olive oil feeding period, oleic acid concentrations were increased in the stored triacylglycerols (45) and also incorporated into the plasma membrane phospholipids (46) in both perirenal and subcutaneous WAT. Although not measured, it can be expected that the same would be true for the triacylglycerols stored in IBAT, skeletal muscle, and mitochondrial membranes. This potential increase in oleic acid might modify the response of IBAT and gastrocnemius muscle to adrenaline. Furthermore, the modifications in membrane phospholipids could lead to modifications of the membrane-receptor interactions of the transduction of the hormonal signal (23, 47–49). So while olive oil didn't increase BAT activity per se, it did increase UCP gene expression and whole body oxygen consumption - perhap through UCP3-mediated mitochondrial uncoupling in skeletal muscles. If challenged by cooler temperatures and/or less food, I strongly suspect these increases in UCP gene activity would have also resulted in increased BAT activity. So I'm going to take the liberty of adding olive oil to the master list of BAT promoters. Here is the latest full list of modifiable and [non-modifiable] factors associated with increased BAT quantity and/or activity: Cold exposure - by far the best BAT inducer/activator Spicy / pungent foods, herbs & supplements - capsaicin / chilli peppers, curcumin / turmeric root, menthol/mint/camphor, oregano, cloves, mustard, horseradish/wasabi, garlic, onions Arginine-rich foods - Good vegan sources include seeds (esp. sesame, sunflower & pumpkin), nuts (esp. almonds and walnuts) and legumes (esp. soy, lupin & fava beans and peas) Other foods - green tea, roasted coffee, cacao beans / chocolate Drugs - metformin, caffeine Avoiding gluten Olive Oil / MUFA-rich diet Methionine restriction - Reduce animal protein. Soy is low in methionine and high in arginine (see below). Low protein diet Fasting Exercise Avoid obesity/overweight [being naturally thin - high metabolic rate] [being younger] [being female] [Ethnicity - having cold-climate ancestors] Once again we see a food or behavior, in this case consumption of olive oil / MUFA, which is known to promote health / longevity also be a (likely) promoter of BAT activity - perhaps when coupled with cold exposure. You can judge for yourself whether all of these are coincidence or not... P.S. I've edited the cold exposure and immunity post by adding this study (PMID: 10444630), which basically reinforces the conclusion that very serious cold exposure in humans (sitting wearing just shorts in 5°C with slightly breeze for 2 hours) elevates immune system activity. P.P.S. I'm happy to report that this thread is #6 on the first page of results when you (or at least when I) do a Google search for "cold exposure longevity". --Dean ------------  Am J Clin Nutr. 2002 Feb;75(2):213-20. Olive oil feeding up-regulates uncoupling protein genes in rat brown adipose tissue and skeletal muscle. Rodríguez VM(1), Portillo MP, Picó C, Macarulla MT, Palou A. Author information: (1)Department of Nutrition and Food Science, the University of País Vasco, Vitoria, Spain. Free full text: http://ajcn.nutrition.org/content/75/2/213.long BACKGROUND: Some nutrients, such as carotenoids, retinoic acid, and certain types of fatty acids, increase thermogenic capacity. OBJECTIVE: The influence of 4 dietary lipid sources (olive oil, sunflower oil, palm oil, and beef tallow) on the content of uncoupling proteins 1, 2, and 3 (UCP1, UCP2, and UCP3) and their messenger RNA (mRNA) expression in several tissues of rats was compared. DESIGN: Wistar rats were randomly divided into 4 groups and fed ad libitum diets containing 40% of energy as fat. UCP1, UCP2, and UCP3 mRNA and protein were assessed by Northern blot and Western blot, respectively. Oxygen consumption in tissues was measured by polarography. Total-body oxygen consumption was assessed in an open-circuit chamber system. Circulating fuels (fatty acids and glucose) and hormones (triiodothyronine, thyroxine, corticosterone, and insulin) were measured. RESULTS: Olive oil feeding induced the highest UCP1, UCP2, and UCP3 mRNA expression in interscapular brown adipose tissue. An analogous effect was observed in gastrocnemius muscle UCP3 mRNA. No significant differences were observed in perirenal white adipose tissue UCP2 mRNA. Changes in mRNAs were not accompanied by close changes in the protein content of UCPs and were not associated with changes in adipose tissue oxygen consumption. Nevertheless, total-body oxygen consumption was higher in rats fed olive oil than in those fed the other 3 diets. No significant differences were found in body and tissue weights or in serum indexes. CONCLUSION: Olive oil induced an up-regulating effect on UCP mRNA that was probably not mediated by systemic metabolic changes, but rather related to a local effect on interscapular brown adipose tissue and skeletal muscle. PMID: 11815310
Cold Exposure Reduces Exercise-Induced Inflammation and Elevation in Testosterone / IGF-1 After that huge post, while waiting for Michael's response, I figured I'd share a short and relatively straightforward study , on the effects of combining cold exposure (CE) and exercise in humans. I think it's safe to say that virtually every CRer, and in fact everyone seriously concerned with their health, engages in some form of exercise for its CVD-preventing, muscle-preserving and bone-building benefits. But some of us worry about the effects of the inflammation and the 'wear-and-tear' associated with exercise, particularly as we get older. And we aren't really interested in the getting big muscles, or raising our growth- and age-promoting testosterone & IGF-1 levels. In addition, some of us (well, maybe just me☺) who nearly continuously expose ourselves to cold, combine it with nearly continuous very modest exercise for several reasons: to keep the blood circulating in the cold, to burn calories to maintain a net calorie deficit, and for all the wonderful benefits of CE described in my previous post and elsewhere in this thread. But I've been a bit worried about the possible deleterious impact of combining CE and exercise. Might the extra physiological stress resulting from CE + exercise magnify the exercise-induced inflammation, and result in the accumulation of the kind of systemic damage that is the hallmark of aging - or more accurately, according to the SENS perspective, that is aging? Fortunately, it looks like this is not the case - in fact quite the opposite. Study  found that relative to exercising in at room temperature, exercising at 0°C in shorts and a t-shirt (that's my kind of experiment!) resulted in the reduction of a wide range of inflammatory and growth promoting markers, including many interleukins and a bunch of others cytokines, several of which I've never heard of, including IFN-γ, Rantes, Eotaxin, IP-10, MIP-1β, MCP-1, VEGF, PDGF, and G-CSF [see Note 1]. Adding CE to exercise also blunted the exercise-induced increase in lymphocytes (white blood cells), which is also considered an inflammatory response. Reduced lymphocytes is a well known side effect of CR as well, although there is some reason to be concerned that this could negatively impact one's ability to fight off an established illness, as discussed here. Adding CE to exercise also blunted the exercise-induced increase in testosterone and IGF-1. This too resembles the testosterone and IGF-1 lowering effects of long-term CR. Interestingly, if they really tortured the subjects, by exposing them to a "pre-exercise low-intensity shivering protocol" (having them sit idle for 40-120min in 0°C in only shorts & t-shirt!) plus continued cold exposure during the subsequent exercise session, the combination reversed some of the beneficial reduction in inflammation and exacerbated the reduction in lymphocytes induced by exercising in the cold. It seems that bringing subjects to the point of shivering and then having them exercise in the cold was going too far to be beneficial. In a similar fashion,  found that chronic cold water exposure (without exercise, and to the point of inducing shivering) resulted in a modest elevation in markers of immune system activity, and a trend towards increased lymphocytes also. This result is corroborated by , which found that exposing men to 2 hours of a 5°C environment with a breeze blowing on them while wearing just shorts and socks boosted immune system activity, especially if the CE is preceded by exercise. So if you are concerned about suppressed immunity as a result of CR or some other malady, and you want to increase immune system activity, CE to the point of shivering, perhaps in association with exercise, might be a way to do it. Here is the summary from the authors of : This study demonstrated that exercising in the cold can diminish the exercise-induced systemic inflammatory response seen in a thermoneutral environment. Nonetheless, prolonged cooling inducing shivering thermogenesis prior to exercise, may induce an immuno-stimulatory response following moderate intensity exercise. Performing exercise in cold environments can be a useful strategy in partially inhibiting the acute systemic inflammatory response from exercise but oppositely, additional body cooling may reverse this benefit. In short, it appears the combination of non-shivering cold exposure + exercise is a win relative to exercise-alone when it comes to inflammation and pro-aging growth factors like testosterone and IGF-1. If you want to boost your immune system, cold exposure to the point of shivering looks to be an option. --Dean Note 1: The reduction of VEGF by cold exposure is interesting since elevated levels are implicated in a variety of cancers as well as macular degeneration, the latter of which is of particular concern for me. ----------  PLoS One. 2014 Oct 22;9(10):e110774. doi: 10.1371/journal.pone.0110774. eCollection 2014. The effects of cold exposure on leukocytes, hormones and cytokines during acute exercise in humans. Gagnon DD(1), Gagnon SS(2), Rintamäki H(3), Törmäkangas T(4), Puukka K(5), Herzig KH(6), Kyröläinen H(7). Free full text: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0110774 The purpose of the study was to examine the effects of exercise on total leukocyte count and subsets, as well as hormone and cytokine responses in a thermoneutral and cold environment, with and without an individualized pre-cooling protocol inducing low-intensity shivering. Nine healthy young men participated in six experimental trials wearing shorts and t-shirts. Participants exercised for 60 min on a treadmill at low (LOW: 50% of peak VO2) and moderate (MOD: 70% VO2peak) exercise intensities in a climatic chamber set at 22°C (NT), and in 0°C (COLD) with and without a pre-exercise low-intensity shivering protocol (SHIV). Core and skin temperature, heart rate and oxygen consumption were collected continuously. Blood samples were collected before and at the end of exercise to assess endocrine and immunological changes. Core temperature in NT was greater than COLD and SHIV by 0.4±0.2°C whereas skin temperature in NT was also greater than COLD and SHIV by 8.5±1.4°C and 9.3±2.5°C respectively in MOD. Total testosterone, adenocorticotropin and cortisol were greater in NT vs. COLD and SHIV in MOD. Norepinephrine was greater in NT vs. other conditions across intensities. Interleukin-2, IL-5, IL-7, IL-10, IL-17, IFN-γ, Rantes, Eotaxin, IP-10, MIP-1β, MCP-1, VEGF, PDGF, and G-CSF were elevated in NT vs. COLD and/or SHIV. Furthermore, IFN-γ, MIP-1β, MCP-1, IL-10, VEGF, and PDGF demonstrate greater concentrations in SHIV vs. COLD, mainly in the MOD condition. This study demonstrated that exercising in the cold can diminish the exercise-induced systemic inflammatory response seen in a thermoneutral environment. Nonetheless, prolonged cooling inducing shivering thermogenesis prior to exercise, may induce an immuno-stimulatory response following moderate intensity exercise. Performing exercise in cold environments can be a useful strategy in partially inhibiting the acute systemic inflammatory response from exercise but oppositely, additional body cooling may reverse this benefit. PMCID: PMC4206434 PMID: 25338085 -----------  Eur J Appl Physiol Occup Physiol. 1996;72(5-6):445-50. Immune system of cold-exposed and cold-adapted humans. Janský L(1), Pospísilová D, Honzová S, Ulicný B, Srámek P, Zeman V, Kamínková J. Author information: (1)Department of Comparative Physiology, Faculty of Science, Charles University Vinicná 7, Prague, Czech Republic. The aim of this study was to investigate whether or not the human immune system can be activated by a noninfectious stimulus, thereby improving the physiological status of the individual. The effect of a single cold water immersion (14 degrees C for 1 h) on the immune system of athletic young men, monitored immediately after immersion, was minimal. With the continuation of the cold water immersions (three times a week for a duration of 6 weeks) a small, but significant, increase in the proportions of monocytes, lymphocytes with expressed IL2 receptors (CD25) and in plasma tumour necrosis factor alpha content was induced. An increase in the plasma concentrations of some acute phase proteins, such as haptoglobin and haemopexin, was also observed. After 6 weeks of repeated immersions a trend towards an increase in the plasma concentrations of IL6 and the amount of total T lymphocytes (CD3), T helper cells (CD4), T suppressor cells (CD8), activated T and B lymphocytes (HLA-DR) and a decrease in the plasma concentration of alpha 1-antitrypsin was observed. Concentrations of IL1 beta, neopterin, C-reactive protein, orosomucoid, ceruloplasmin, macroglobulin, immunoglobulins (IgG, IgM, IgA) and C3, C4 components of the complement, as well as the total number of erythrocytes, leucocytes, granulocytes and neutrophils showed no significant changes after the repeated cold water immersions. It was concluded that the stress-inducing noninfectious stimuli, such as repeated cold water immersions, which increased metabolic rate due to shivering the elevated blood concentrations of catecholamines, activated the immune system to a slight extent. The biological significance of the changes observed remains to be elucidated. PMID: 8925815 --------  J Appl Physiol (1985). 1999 Aug;87(2):699-710. Immune changes in humans during cold exposure: effects of prior heating and exercise. Brenner IK(1), Castellani JW, Gabaree C, Young AJ, Zamecnik J, Shephard RJ, Shek PN. Author information: (1)Defence and Civil Institute of Environmental Medicine, Toronto, Ontario M3M 3B9. Free full text: http://jap.physiology.org/content/87/2/699 This study examined the immunological responses to cold exposure together with the effects of pretreatment with either passive heating or exercise (with and without a thermal clamp). On four separate occasions, seven healthy men [mean age 24.0 +/- 1.9 (SE) yr, peak oxygen consumption = 45.7 +/- 2.0 ml. kg(-1). min(-1)] sat for 2 h in a climatic chamber maintained at 5 degrees C. Before exposure, subjects participated in one of four pretreatment conditions. For the thermoneutral control condition, subjects remained seated for 1 h in a water bath at 35 degrees C. In another pretreatment, subjects were passively heated in a warm (38 degrees C) water bath for 1 h. In two other pretreatments, subjects exercised for 1 h at 55% peak oxygen consumption (once immersed in 18 degrees C water and once in 35 degrees C water). Core temperature rose by 1 degrees C during passive heating and during exercise in 35 degrees C water and remained stable during exercise in 18 degrees C water (thermal clamping). Subsequent cold exposure induced a leukocytosis and granulocytosis, an increase in natural killer cell count and activity, and a rise in circulating levels of interleukin-6. Pretreatment with exercise in 18 degrees C water augmented the leukocyte, granulocyte, and monocyte response. These results indicate that acute cold exposure has immunostimulating effects and that, with thermal clamping, pretreatment with physical exercise can enhance this response. Increases in levels of circulating norepinephrine may account for the changes observed during cold exposure and their modification by changes in initial status. PMID: 10444630