Cold Exposure & Other Mild Stressors for Increased Health & Longevity

[Saul]

Hi Ron!

Thanks for your thoughtful post.

  --  Saul

[mccoy]

21 hours ago, Ron Put said:

One curious item: "... the same gene, TRPA-1 that is activated by cold in worms and mammals can also be triggered by eating Japanese horseradish (wasabi)" A much more pleasant way to activate it, IMO. I'll try it at dinner tonight. 🙂

The definition of 'pleasant' may be pretty subjective. Most of people here, me included, find it pretty pleasant to feel the cold and the adaptive response of the body to it.

Some people just won't tolerate it, but often it appears to be more of a mental issue or rejection.

Also as Dean says it's very advisable to approach CE with caution, starting with mildly cold or cool temperatures and short exposures. It's good to start from the fall, getting accustomed to the progressive decrease in air and water temperatures. And really cold water causes a sudden release of norepinephrine with the consequent spike in blood pressure. Exposure should not be sudden: first a foot, then the leg, then spraying the torso and so on...

[Ron Put]

19 hours ago, Dean Pomerleau said:

Ron, 

Read this post for a response to your skepticism.

Regarding the potential negative effects of acute cold exposure, the benefits of CE require acclimatization, and shouldn't be undertaken by the anyone at risk of cardiovascular events. Similar to strenuous exercise. 

Dean 

Thanks. I am still not convinced that exposure to cold has a significant long-term benefit in humans. For every other major factor, such exercise, diet, caloric restriction, we can find statistically significant trends in population studies.

For cold exposure, the trends are generally negatively associated with longevity. Here is another, larger study:

"Cold weather kills 20 times as many people as hot weather, according to an international study analyzing over 74 million deaths in 384 locations across 13 countries. ...

Around 7.71% of all deaths were caused by non-optimal temperatures, with substantial differences between countries, ranging from around 3% in Thailand, Brazil, and Sweden to about 11% in China, Italy, and Japan. Cold was responsible for the majority of these deaths (7.29% of all deaths), while just 0.42% of all deaths were attributable to heat." 
https://www.sciencedaily.com/releases/2015/05/150520193831.htm

I understand that such population studies have their shortcomings. But I will repeat that one would expect that if long-term cold exposure was of significant benefit to human longevity, we would see a higher proportion of extraordinary longevity in populations subjected to such exposure, yet, we see the opposite (regardless of income and healthcare access):



 

Edited June 7, 2019 by Ron Put

[Todd Allen]

1 hour ago, Ron Put said:

For cold exposure, the trends are generally negatively associated with longevity. Here is another, larger study:

"Cold weather kills 20 times as many people as hot weather,

Dean pointed out that CE is a hormetic stressor similar to exercise.  To be beneficial the dose must be within ones tolerance.  If ones tolerance is poor as is common with advanced age and especially sickness then CE is a potentially fatal stressor.  Being able to control exposure is key.

 

[Dean Pomerleau]

Ron,

By your same argument, one might expect to see extended longevity in countries with frequent food shortages, like South Sudan or Yemen, since many of its citizens be naturally subject to calorie restriction. Or we should expect to see extended longevity as a result of a high proportion of vegetarians in countries like India, as Todd Allen speciously tried to argue on another thread.

There are just too many confounders in human populations. Here is an interesting one. There is some evidence (e.g. [1]), that the circadian rhythm disruption resulting from living at higher latitudes or at certain positions within a (longitudinal) time zone is associated with cancer and all-cause mortality. If true, this could quite conceivably mask any benefits of extra (potential) cold exposure associated with living at a higher latitude.

Conversely, in the US, people living at more northern latitudes do live longer than southerners. Should I crow about this as evidence in favor of cold exposure? Clearly not. There are many more important causes of the north/south discrepancy in US longevity that any benefits of CE would be swamped in the data. This shows the silliness of looking to human population-level epidemiological data for evidence of longevity benefits of specific interventions like cold exposure. 

Moreover, the typical oldster who reaches 100 does so as a result of freakishly good genes (and possibly good healthcare), not because of their meticulous lifestyle choices, since so few people make the kind of comprehensive and sometimes challenging lifestyle choices we do and sticks with them for decades. So expecting to see statistical evidence to support longevity benefits of CE (or CR) in the tiny fraction of people who are lucky enough to make it to 100 is like looking for a needle in a haystack.

Plus, cold outdoor temperatures have very little correlation with the temperature people are exposed to for any length of time during the day, particularly well-educated people in affluent first world countries living at northern latitudes (with indoor heat and AC) who are likely to be the only ones with any chance of making the prerequisite good lifestyle choices and have access to good medical care to avoid the typical diseases of affluence that cut lifespan short before any benefits of CE (or CR) become manifest.

Furthermore, I said I don't expect CE alone to extend (maximum) lifespan, or help someone reach 100. I said that pretty strong evidence suggests that CR is effective in rodents only when coupled with CE.  As a corollary, it stands to reason that if serious CR can significantly extend human lifespan (which I seriously doubt BTW), it likely needs to be coupled with CE. It seems virtually certain that there no significant population anywhere in the world that practices significant CR with good nutrition and cold exposure, not to mention having access to good medical care, and engaging in exercise to maintain CV health, etc to test this hypothesis.

In summary, expecting to see support of the longevity benefits of CE (or CR, or CR+CE) in country-wide or "Blue Zone" epidemiological data is a fool's errand. At best you might hope to see support for benefits of the "low hanging fruit" when it comes to diet and lifestyle choices ( e.g. exercise, healthy diet - mostly plant-based, healthy weight, don't smoke, etc.), since those are the only interventions likely to be practiced by enough of the population to show up in the data.

Even then I wouldn't trust epidemiological evidence except as a hint to look for more direct evidence, due to presence of so much heterogeneity and confounders when studying large human populations. The only possible exception might be relatively homogeneous sub-populations which can serve as their own control group due to internal variability - like Californian Adventists, some of whom are vegetarian and others who aren't but who otherwise have relatively similar social, economic, and lifestyle characteristics.

--Dean

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

[1] Chronobiol Int. 2011 Mar;28(2):155-62. doi: 10.3109/07420528.2010.541312.

Latitude of residence and position in time zone are predictors of cancer incidence, cancer mortality, and life expectancy at birth.

Borisenkov MF(1). Author information: (1)Institute of Physiology, Komi Science Centre, Ural Branch of Russian Academy of Science, Syktyvkar, Russia. borisenkov@physiol.komisc.ru

Comment in Chronobiol Int. 2011 May;28(5):471-3; author reply p 473.

According to the hypothesis of circadian disruption, external factors that disturb the function of the circadian system can raise the risk of malignant neoplasm and reduce life span. Recent work has shown that the functionality of the circadian system is dependent not only on latitude of residence but also on the region's position in the time zone. The purpose of the present research was to examine the influence of latitude and time zone on cancer incidence, cancer mortality, and life expectancy at birth. A stepwise multiple regression analysis was carried out on residents of 59 regions of the European part of the Russian Federation (EPRF) using age-standardized parameters (per 100,000) of cancer incidence (CI), cancer mortality (CM), and life expectancy at birth (LE, yrs) as dependent variables. The geographical coordinates (latitude and position in the time zone) of the regions were used as independent variables, controlling for the level of economic development in the regions. The same analysis was carried out for LE in 31 regions in China. Latitude was the strongest predictor of LE in the EPRF population; it explained 48% and 45% of the variability in LE of women and men, respectively. Position within the time zone accounted for an additional 4% and 3% variability of LE in women and men, respectively. The highest values for LE were observed in the southeast of the EPRF. In China, latitude was not a predictor of LE, whereas position in the time zone explained 15% and 18% of the LE variability in women and men, respectively. The highest values of LE were observed in the eastern regions of China. Both latitude and position within the time zone were predictors for CI and CM of the EPRF population. Latitude was the best predictor of stomach CI and CM; this predictor explained 46% and 50% of the variability, respectively. Position within the time zone was the best predictor of female breast CM; it explained 15% of the variability. In most cases, CI and CM increased with increasing latitude of residence, from the eastern to the western border of the time zone, and with increasing level of economic development within the region. The dependence of CI, CM, and LE on the geographical coordinates of residence is in agreement with the hypothesis of circadian disruption. DOI: 10.3109/07420528.2010.541312 PMID: 21231877

 

[Ron Put]

On 6/7/2019 at 3:44 PM, Dean Pomerleau said:

Ron,

By your same argument, one might expect to see extended longevity in countries with frequent food shortages, like South Sudan or Yemen, since many of its citizens be naturally subject to calorie restriction. Or we should expect to see extended longevity as a result of a high proportion of vegetarians in countries like India, as Todd Allen speciously tried to argue on another thread.

... There are just too many confounders in human populations. Here is an interesting one. There is some evidence (e.g. [1]), that the circadian rhythm disruption resulting from living at higher latitudes or at certain positions within a (longitudinal) time zone is associated with cancer and all-cause mortality. If true, this could quite conceivably mask any benefits of extra (potential) cold exposure associated with living at a higher latitude.

Conversely, in the US, people living at more northern latitudes do live longer than southerners. Should I crow about this as evidence in favor of cold exposure? ...

Even then I wouldn't trust epidemiological evidence except as a hint to look for more direct evidence, due to presence of so much heterogeneity and confounders when studying large human populations. The only possible exception might be relatively homogeneous sub-populations which can serve as their own control group due to internal variability - like Californian Adventists, some of whom are vegetarian and others who aren't but who otherwise have relatively similar social, economic, and lifestyle characteristics.

...

Actually, there are a number of appropriate population studies which correlate both calorie/protein restriction and plant diets, with lower mortality/longevity. In addition to Okinawa and Sardinia, there are also other examples of populations which experienced significant caloric restriction, without malnutrition:

"During World War 1 in 1917, Danish men and women were forced to reduce food consumption for 2 years, but with a well-planned and adequate consumption of whole grain cereals, vegetables, and milk. The result of this undesired experiment was an impressive 34% reduction in death rates (Hindhede, 1920). Similarly, in Norway during World War 2, the citizens of Oslo underwent a forced 20% CR without malnutrition (i.e. Norwegians were provided with adequate intake of fresh vegetables, potatoes, fish and whole cereals) for approximately 4 years (1941-45). In this forced experiment, mortality dropped by 30% compared to the pre-war level in both men and women (Strom and Jensen, 1951)". https://www.draisistoledo.com/wp-content/uploads/Calorie-restriction-in-humans-An-update.pdf

I am not aware of any similar population results showing correlation with cold exposure.

As to some of the examples above, we must differentiate between caloric restriction and malnutrition. Just as we must take into account regional lifestyle, education, diet and access to healthcare (all of these are generally worse in the southern US).

Anyway, while I am aware of the lab results, I still remain skeptical of long term benefits in humans.

If someone enjoys cold showers and ice dunks, that's a different matter, of course. :)

[Dean Pomerleau]

11 hours ago, Ron Put said:

... there are also other examples of populations which experienced significant caloric restriction, without malnutrition:

"During World War 1 in 1917, Danish men and women were forced to reduce food consumption for 2 years, but with a well-planned and adequate consumption of whole grain cereals, vegetables, and milk. The result of this undesired experiment was an impressive 34% reduction in death rates (Hindhede, 1920). Similarly, in Norway during World War 2, the citizens of Oslo underwent a forced 20% CR without malnutrition (i.e. Norwegians were provided with adequate intake of fresh vegetables, potatoes, fish and whole cereals) for approximately 4 years (1941-45). In this forced experiment, mortality dropped by 30% compared to the pre-war level in both men and women (Strom and Jensen, 1951)."

Ron, 

It's interesting that the two examples you give of populations that benefited from forced CR during wartime (Denmark and Norway) are two of the northernmost countries in Europe. In fact, the city of Oslo which you cite as evidence for the benefits of CR is one of the top 10 coldest cities in Europe, with a year round average high temperature of 49F (10C) and low of 36F (2C).

So I take it back. It appears there is epidemiology evidence that human longevity benefits may result from the combination of CR and CE. I still don't think such evidence is worth very much, but thanks for pointing it out. 

Dean 

 

[Sibiriak]

Quote

Ron Put: in places with long, severe winters, the average resident is exposed, over a lifetime, to lower temperatures for longer periods than someplace like Costa Rica or Sardinia

 

Btw,  I'm from California but live in Siberia now which has long, severe winters,  and I can assure you,  the average Siberian is exposed to warmer average temperatures than an average Californian. 

Edited June 10, 2019 by Sibiriak

[Ron Put]

4 hours ago, Dean Pomerleau said:

... So I take it back. It appears there is epidemiology evidence that human longevity benefits may result from the combination of CR and CE. I still don't think such evidence is worth very much, but thanks for pointing it out. 

Dean 

 

Haha. Of course, these studies compare the same population in restricted calories state and in free feeding state. And restricting calories appears to be beneficial in terms of lower mortality rates.

However, the longevity of the Scandinavians is still lower than that of the Mediterraneans, as per my post above. Cold exposure, higher incomes and better access to more advanced healthcare up North notwithstanding.

Edited June 10, 2019 by Ron Put

[Dean Pomerleau]

Cold Exposure and Glucose Revisited

A couple posts ago on this thread I said that the evidence in favor of cold exposure for glucose control, and therefore avoidance of type 2 diabetes was "incontrovertible." Here are a couple recent papers supporting this conclusion.

The first [1] represented the kind of epidemiology evidence that Ron might appreciate :-).

It looked at ~5000 Spanish adults, correlating their rate of pre-diabetes, diabetes and insulin resistance (measured by an oral glucose tolerance test) with the mean annual temperature of their hometown. There was a pretty dramatic direct correlation, even after accounting for a host of potential confounders, including "multiple socio-demographic variables, lifestyle, adiposity (BMI) and geographical elevation." They found that rate of diabetes was 39% lower in people who lived in the coldest part of Spain compared with the warmest. The authors concluded there result are:

Quote

...consistent with the hypothesis that a lower exposure to cold could be associated with a higher risk of metabolic derangements.

The second study [2], was interventional. The authors exposed 15 healthy men to both thermoneutral conditions (72F, 22C) and cold exposure (64F, 18C) via a whole body suit. They found that cold exposure improved glucose uptake and insulin sensitivity by 20% without increasing insulin secretion from the pancreas. They conclude:

Quote

These data support the concept that human BAT metabolism significantly contributes to whole body glucose and lipid utilization in a coordinated manner.

Avoiding diabetes is important in its own right, given how prevelant it has become in western society. But improved glucose metabolism also may explain why it appears important to combine CR with CE to achieve longevity benefits. One of the most important ways CR seems to boost lifespan (in rodents, where it has been demonstrated) is by downregulating insulin and the pro-aging insulin signaling pathway, thereby shifting the organism into a metabolic mode which emphasizes maintenence and repair rather than growth and reproduction. 

But without much insulin around, glucose has a tendency to get stuck in the bloodstream unable to enter cells, an effect some of us have experienced first hand. Elevated circulating glucose has negative long-term health and longevity consequences as illustrated by the ravages of diabetes. 

Adding cold exposure on top of CR may overcome this potential Achille's heal of CR alone by boosting metabolically-active brown/beige adipose tissue (BAT) to serve as a sink for circulating glucose.

--Dean 

--------

[1] Eur J Endocrinol. 2019 May 1;180(5):273-280. doi: 10.1530/EJE-18-0818.

Ambient temperature and prevalence of diabetes and insulin resistance in the Spanish population: Di@bet.es study.

Valdés S(1)(2), Doulatram-Gamgaram V(1), Lago A(1)(2), García Torres F(3), Badía-Guillén R(1), Olveira G(1)(2), Goday A(4), Calle-Pascual A(2)(5), Castaño L(2)(6)(7), Castell C(8), Delgado E(9), Menendez E(9), Franch-Nadal J(2)(10), Gaztambide S(2)(11)(7), Girbés J(12), Gomis R(2)(13), Ortega E(13)(14), Galán-García JL(15), Aguilera-Venegas G(15), Soriguer F(1)(2), Rojo-Martínez G(1)(2). 

Objective: The activity of brown adipose tissue is sensitive to changes in ambient temperature. A lower exposure to cold could result in an increased risk of developing diabetes at population level, although this factor has not yet been sufficiently studied. Design We studied 5072 subjects, participants in a national, cross-sectional population-based study representative of the Spanish adult population (Di@bet.es study). All subjects underwent a clinical, demographic and lifestyle survey, a physical examination and blood sampling (75 g oral glucose tolerance test). Insulin resistance was estimated with the homeostasis model assessment (HOMA-IR). The mean annual temperature (°C) in each individual municipality was collected from the Spanish National Meteorology Agency. Results Linear regression analysis showed a significant positive association between mean annual temperature and fasting plasma glucose (β: 0.087, P < 0.001), 2 h plasma glucose (β: 0.049, P = 0.008) and HOMA-IR (β: 0.046, P = 0.008) in multivariate adjusted models. Logistic regression analyses controlled by multiple socio-demographic variables, lifestyle, adiposity (BMI) and geographical elevation showed increasing odds ratios for prediabetes (WHO 1999), ORs 1, 1.26 (0.95-1.66), 1.08 (0.81-1.44) and 1.37 (1.01-1.85) P for trend = 0.086, diabetes (WHO 1999) ORs 1, 1.05 (0.79-1.39), 1.20 (0.91-1.59) and 1.39 (1.02-1.90) P = 0.037, and insulin resistance (HOMA-IR ≥75th percentile of the non-diabetic population): ORs 1, 1.03 (0.82-1.30), 1.22 (0.96-1.55), 1.26 (0.98-1.63) (P for trend = 0.046) as the mean annual temperature (into quartiles) rose.

Conclusions: Our study reports an association between ambient temperature and the prevalence of dysglycemia and insulin resistance in Spanish adults, consistent with the hypothesis that a lower exposure to cold could be associated with a higher risk of metabolic derangements.

DOI: 10.1530/EJE-18-0818

PMID: 30840583

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

[2] J Clin Endocrinol Metab. 2017 Nov 1;102(11):4226-4234. doi: 10.1210/jc.2017-01250.

Cold-Induced Brown Adipose Tissue Activity Alters Plasma Fatty Acids and Improves Glucose Metabolism in Men.

Iwen KA(1), Backhaus J(1), Cassens M(1), Waltl M(1), Hedesan OC(2), Merkel M(3), Heeren J(4), Sina C(5), Rademacher L(1), Windjäger A(1), Haug AR(6), Kiefer FW(2), Lehnert H(1)(7), Schmid SM(1)(7).

Context: Mounting evidence suggests beneficial effects of brown adipose tissue (BAT) activation on glucose and lipid metabolism in humans. It is unclear whether cold-induced BAT activation affects not only insulin sensitivity but also insulin secretion. Likewise, the role in clearing circulating fatty acids (FAs) has not been fully explored. Objective: Exploring the effects of cold-induced BAT activation on insulin sensitivity and secretion, as well as on plasma FA profiles. Design: Fifteen healthy men participated in a cross-balanced repeated within-subject study with two experimental conditions. Subjects were exposed to thermoneutrality (22°C) and to moderate cold (18.06°C, shivering excluded) by use of a water-perfused whole body suit. Cold-induced BAT activation was quantified by [18F]-fluorodeoxyglucose positron emission tomography-computed tomography in a subset of volunteers. A Botnia clamp procedure was applied to determine pancreatic first phase insulin response (FPIR) and insulin sensitivity. Hormones and metabolites, including 26 specific plasma FAs, were sampled throughout the experiment. Results: Cold exposure induced BAT activity. Plasma noradrenaline and dopamine concentrations increased in response to cold. Peripheral glucose uptake and insulin sensitivity significantly improved by ∼20%, whereas FPIR remained stable. Lignoceric acid (C24:0) concentrations increased, whereas levels of eicosanoic acid (C20:1n9), nervonic acid (C24:1n9), and behenic acid (C22:0) decreased. Conclusions: Cold-exposure induces sympathetic nervous system activity and BAT metabolism in humans, resulting in improved glucose metabolism without affecting pancreatic insulin secretion. In addition, BAT activation is associated with altered circulating concentrations of distinct FAs. These data support the concept that human BAT metabolism significantly contributes to whole body glucose and lipid utilization in a coordinated manner. Copyright © 2017 Endocrine Society

DOI: 10.1210/jc.2017-01250

PMID: 28945846

[Gordo]

Personally I think the evidence for CE is more compelling than the evidence for serious CR.  As Dean pointed out, "To summarize, in species that span a wide range of latitudes, the within-species longevity is pretty strongly correlated with how far north (or south in the southern hemisphere) an individual lives. That is, cooler environments → increased lifespan across a huge range of land, freshwater and marine species."   Humans on the other hand, live in climate controlled environments, so no matter where they live, they rarely get any cold exposure.  And yet we can, and have, observed positive physiological changes in humans as a result of cold exposure.  I summarized a lot of the findings here.

As for Okinawans - for MEN, the longevity increase was less than one year compared to mainland Japanese men, oh, and also less favorable compared to the CA adventists who don't do CR (but do for the most part eat a plant based whole food diet and some fish).  The lack of junk food, strong community, and lower stress living probably mean a lot more for longevity than restricting calories.

Speaking of men and longevity, it is interesting to note that for MEN, the top 2 countries in the world for life expectancy are Switzerland and Iceland.

I enjoyed this article: 

THE LAND THAT DEATH FORGOT

Type in the latitude and longitude for longevity, and you’ll arrive at Iceland. Here’s why.

[TomBAvoider]

That graphic about the economies with the biggest percentage of centenarians is an example of data that is meaningless. The primary reason is the most fundamental - the integrity of the data is abysmal. Even in a highly developed country, with presumably excellent records - like Japan. Here is the Japanese scam with regard to centenarians:

https://www.bbc.com/news/world-asia-pacific-11258071

Executive summary: vast numbers of centenarians in Japan are fictional - people's deaths are not recorded so that families may continue to draw pension benefits. I wouldn't trust longevity statistics coming out of Japan, period.

The other countries are just ludicrous if you know anything about the realities on the ground - Uruguay, Dominican Republic, Chile - LOL. The records over there are worth exactly nothing, with vast numbers of people whose birth records are approximate at best, so good luck trying to establish age based on such. You can't base any kind of age analysis on records this poor. Places like Vietnam, that have experienced war and displacement on a vast scale, have seriously distorted demographic numbers due to people dying, emigrating and being displaced. When you have people fleeing in vast numbers, it's almost never the very old, so what is left behind is a distorted age group - they are not a consistent cohort who have gone through all the natural stages of birth and death in their natural numbers. Such stats are meaningless. 

With the possible exception of Scandinavian countries (Finland too is iffy, on account of WWII), you should not place too much faith in the age-distribution of the population as saying much of anything about longevity factors. 

And when it comes to supercentenarians the situation grows even worse due to the tiny numbers. You are left with essentially anecdotes. Jeanne Calment is a wild outlier with no one even coming close - and now serious questions have been raised as to how legitimate her age actually was (see the thread I started about this). And what conclusion should you reach about DIET when the oldest man (112+ yo) for a while was a Jewish immigrant to Israel who lived through years of ghetto starvation and concentration camps - how good do you suppose his diet was during that years long time? Btw. his profession was a candymaker - do you suppose he ever dipped into his own production? Or maybe you want to reach conclusions about COLD and geographic lattitude based on this fellow, who spent decades in one of the hottest spots on earth, Israel. 

Put me down as deeply suspicious of the whole hype about Blue Zones. Because I think it's a natural human tendency to try to find and believe in good news. I am very, very skeptical about the integrity of statistics and demographic data coming from any of these places, including Okinawa which saw extreme WWII action, and whose pension system (and all its weaknesses and temptations) is Japanese. 

But that's just me. I suppose I'm cursed by an aversion to hype. 

[TomBAvoider]

Btw., if someone wants to see the kind of considerations involved in validating demographic data wrt. age, especially centenarians, here's an interesting read:

https://www.demogr.mpg.de/books/odense/6/12.htm

I think it shows pretty comprehensively why you should exercise extreme caution in taking statistics coming out of most countries at face value. 

Bottom line: disregard most such comparisons between countries.

[Ron Put]

Well, it's too late (and cold) for me to search now....

Edited June 13, 2019 by Ron Put

[Dean Pomerleau]

This study [1] looks like the best evidence yet that chronic consumption of tea catechins, perhaps in combination with caffeine, activates brown adipose tissue and more than doubles cold-induced thermogenesis, even in people who have little BAT to start with. 

--Dean

Am J Clin Nutr. 2017 Apr;105(4):873-881.  Epub 2017 Mar 8.

Tea catechin and caffeine activate brown adipose tissue and increase cold-induced thermogenic capacity in humans.

Yoneshiro T(1), Matsushita M(2), Hibi M(3), Tone H(3), Takeshita M(3), Yasunaga K(3), Katsuragi Y(3), Kameya T(4), Sugie H(4), Saito M(5).

Background: The thermogenic effects of green tea catechin have been repeatedly reported, but their mechanisms are poorly understood.

Objective: The aim of this study was to investigate the acute and chronic effects of catechin on brown adipose tissue (BAT), a site specialized for nonshivering thermogenesis, in humans.Design: Fifteen healthy male volunteers underwent fluorodeoxyglucose-positron emission tomography to assess BAT activity. To examine the acute catechin effect, whole-body energy expenditure (EE) after a single oral ingestion of a beverage containing 615 mg catechin and 77 mg caffeine (catechin beverage) was measured. Next, to investigate the chronic catechin effects, 10 men with low BAT activity were enrolled. Before and after ingestion of the catechin beverage 2 times/d for 5 wk, cold-induced thermogenesis (CIT) after 2 h of cold exposure at 19°C, which is proportional to BAT activity, was examined. Both the acute and chronic trials were single-blinded, randomized, placebo-controlled, season-matched crossover studies.Results: A single ingestion of the catechin beverage increased EE in 9 subjects who had metabolically active BAT (mean ± SEM: +15.24 ± 1.48 kcal, P < 0.01) but not in 6 subjects who had negligible activities (mean ± SEM: +3.42 ± 2.68 kcal). The ingestion of a placebo beverage containing 82 mg caffeine produced a smaller and comparative EE response in the 2 subject groups. Multivariate regression analysis revealed a significant interaction between BAT and catechin on EE (β = 0.496, P = 0.003). Daily ingestion of the catechin beverage [in people with low BAT activity to start with - DP] elevated mean ± SEM CIT (from 92.0 ± 26.5 to 197.9 ± 27.7 kcal/d; P = 0.009), whereas the placebo beverage [containing caffeine only - DP] did not change it. Conclusion: Orally ingested tea catechin with caffeine acutely increases EE associated with increased BAT activity and chronically elevates nonshivering CIT, probably because of the recruitment of BAT, in humans. 

© 2017 American Society for Nutrition.

DOI: 10.3945/ajcn.116.144972

PMID: 28275131

[Dean Pomerleau]

Ginger Triggers Fat Browning

Here is another medicinal herb to add to the long list of interventions that trigger the formation and/or activation of brown adipose tissue: ginger root.

The new study [1] found that 16 weeks of ginger supplements prevented high-fat diet-induced obesity in mice at least in part by converting white adipose tissue to metabolically active brown/beige adipose tissue (BAT).

Yet another example of a food with recognized health benefits having at least part of its positive effects through boosting BAT.

--Dean

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

• Cold exposure - by far the best BAT inducer/activator
• Spicy / pungent foods, herbs & supplements - capsaicin / chilli peppers, curcumin / turmeric root, menthol/mint/camphor, oregano, cloves, mustard, horseradish/wasabi, garlic, onions
• Sulforaphane-rich foods - Broccoli, brussels sprouts, cabbage
• Nitrate-rich foods - beets, celery, arugula, and spinach
• Arginine-rich foods - Good vegan sources include seeds (esp. sesame, sunflower & pumpkin), nuts (esp. almonds and walnuts) and legumes (esp. soy, lupin & fava beans and peas)
• Citrulline-rich foods - Highest by far in watermelon, but also some in onions, garlic, onions, cucumber, other melons & gourds, walnuts, peanuts, almonds, cocoa, chickpeas
• Luteolin-rich foods - Herbs (thyme, parsley, oregano, peppermint, rosemary), hot peppers, citrus fruit, celery, beets, spinach, cruciferous veggies, olive oil, carrots. 
• Rutin-rich foods - Buckwheat, apple peels, citrus fruit, mulberries, aronia berries, cranberries, peaches, rooibos tea, amaranth leaves, figs
• Healthy Fats - DHA / EPA / fish-oil, MUFA-rich diet,  Extra Virgin Olive Oil
• Fiber - Especially cereal fiber (wheat and oat fiber)
• Olive Polyphenols - Extra Virgin Olive Oil / Olive Leaf Extract / Olive Leaf Tea
• Other foods - Apples / apple peels / ursolic acid; Citrus fruit / citrus peels / limonene; Honey / chrysin
• Beverages - green tea, roasted coffee, red wine, cacao beans / chocolate
• Low gluten diet
• Methionine restriction - Reduce animal protein. Soy is low in methionine and high in arginine, but also high in leucine.
• Leucine restriction - Reduce animals protein. Leucine is highest in beef, fish, eggs, cheese and soy.
• Low protein diet
• Drugs / Supplements - metformin, berberine, caffeine, creatine, nicotinamide riboside (NAD), resveratrol, melatonin
• Medicinal Herbs - ginger root, ginseng, cannabidiol / hemp oil / medicinal marijuana, balloon flower root (Platycodon Grandiflorus)
• Time Restricted Feeding - most calories at breakfast
• Exercise & elevated lactate / lactic acid
• Acupuncture - locations Zusanli (foot - ST36) and Neiting (lower leg - ST44) 
• Whole body vibration therapy
• Avoid obesity/overweight
• Low testosterone / castration in mice (and men?)
• [being naturally thin - high metabolic rate]
• [being younger]
• [being female]
• [Ethnicity - having cold-climate ancestors]
• [being of genotype TT for rs1800592, TT for FTO SNP rs1421085 and AA for rs4994 as reported by 23andMe]

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

[1] J Nutr Biochem. 2019 May 21;70:105-115. doi: 10.1016/j.jnutbio.2019.05.001. [Epub ahead of print]

Ginger prevents obesity through regulation of energy metabolism and activation of browning in high-fat diet-induced obese mice.

Wang J(1), Li D(2), Wang P(2), Hu X(1), Chen F(3). 

Numerous natural herbs have been proven as safe anti-obesity resources. Ginger, one of the most widely consumed spices, has shown beneficial effects against obesity and related metabolic disorders. The present study aimed to examine whether the antiobesity effect of ginger is associated with energy metabolism. Mice were maintained on either a normal control diet or a high-fat diet (HFD) with or without 500 mg/kg (w/w) ginger supplementation. After 16 weeks, ginger supplementation alleviated the HFD-induced increases in body weight, fat accumulation, and levels of serum glucose, triglyceride and cholesterol. Indirect calorimetry showed that ginger administration significantly increased the respiratory exchange ratio (RER) and heat production in both diet models. Furthermore, ginger administration corrected the HFD-induced changes in concentrations of intermediates in glycolysis and the TCA cycle. Moreover, ginger enhanced brown adipose tissue function and activated white adipose tissue browning by altering the gene expression and protein levels of some brown and beige adipocyte-selective markers. Additionally, stimulation of the browning program by ginger may be partly regulated by the sirtuin-1 (SIRT1)/AMP-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) pathway. Taken together, these results indicate that dietary ginger prevents body weight gain by remodeling whole-body energy metabolism and inducing browning of white adipose tissue (WAT). Thus, ginger is an edible plant that plays a role in the therapeutic treatment of obesity and related disorders.

Copyright © 2019. Published by Elsevier Inc.

DOI: 10.1016/j.jnutbio.2019.05.001

PMID: 31200315

[Dean Pomerleau]

This new study [1] found that in mice, lifelong moderate CR (20%) coupled with a cool housing temperature* preserves brown adipose tissue in middle age (12m). This combination of CR + chronic cold exposure also greatly boosts markers of BAT activity in the CRed mice when they were exposed to cold (39F or 4C), as illustrated in the graph below (fig. 5d from [1]).

The dashed horizontal line is the baseline level of each marker (normalized to 1) as measured in 3 month old mice at normal room temperature. When such young mice were exposed to cold, the levels of most of the BAT activity markers rose modestly (light bars) relative to baseline. In contrast, markers of BAT activity remained almost unchanged relative to baseline in AL-fed, middle-aged mice (grey middle bars). But in the modestly CR'ed, middle-aged mice (black bars), the markers of BAT activity shot up when they were exposed to cold.

This aligns nicely with evidence I've presented previously that moderate CR boosts BAT and BAT activity in the presence of modest lifelong cold exposure (i.e. housing rodents at normal room temperature).

The authors suggest this BAT boost is one important mechanism by which CR prevents the metabolic dysfunction associated with aging, especially inflammation and insulin resistance. They conclude:

"In brief, our study identifies the contribution of scWAT [subcutaneous White Adipose Tissue - DP] impairment to age-associated metabolic dysfunction and identifies browning in response to food restriction, as a potential therapeutic strategy to prevent the adverse metabolic effects in middle-aged animals."

--Dean

* The mice were housed at 70F (20C), which is about 10F below mouse's thermoneutral temperature of ~81F (27C). 

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

[1] Aging Cell. 2019 Jun;18(3):e12948. doi: 10.1111/acel.12948. Epub 2019 Mar 28.

Long-term caloric restriction ameliorates deleterious effects of aging on white and brown adipose tissue plasticity.

Corrales P(1), Vivas Y(1), Izquierdo-Lahuerta A(1), Horrillo D(1), Seoane-Collazo P(2)(3), Velasco I(1), Torres L(1), Lopez Y(1), Martínez C(1), López M(2), Ros M(1)(4), Obregon MJ(4)(5), Medina-Gomez G(1)(4). 

Age-related increased adiposity is an important contributory factor in the development of insulin resistance (IR) and is associated with metabolic defects. Caloric restriction (CR) is known to induce weight loss and to decrease adiposity while preventing metabolic risk factors. Here, we show that moderate 20% CR delays early deleterious effects of aging on white and brown adipose tissue (WAT and BAT, respectively) function and improves peripheral IR. To elucidate the role of CR in delaying early signs of aging, young (3 months), middle-aged (12 months), and old (20 months) mice fed al libitum and middle-aged and old mice subjected to early-onset CR were used. We show that impaired plasticity of subcutaneous WAT (scWAT) contributes to IR, which is already evident in middle-aged mice. Moreover, alteration of thyroid axis status with age is an important factor contributing to BAT dysfunction in middle-aged animals. Both defects in WAT and BAT/beige cells are ameliorated by CR. Accordingly, CR attenuated the age-related decline in scWAT function and decreased the extent of fibro-inflammation. Furthermore, CR promoted scWAT browning. In brief, our study identifies the contribution of scWAT impairment to age-associated metabolic dysfunction and identifies browning in response to food restriction, as a potential therapeutic strategy to prevent the adverse metabolic effects in middle-aged animals.

© 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

DOI: 10.1111/acel.12948

PMCID: PMC6516146

PMID: 30920127

[Dean Pomerleau]

Berries Boost BAT

One prominent category of healthy foods that hasn't previously made the long list of interventions that influence brown adipose tissue is berries.

In this sixteen week study [1], researchers spiked the drinking water of obesity/diabetes-prone mice with Cyanidin-3-glucoside (C3G), one of the important anthocyanins found in everyone's favorite dark blue/black/red fruits and particularly berries. Here is a full list of the most C3G-rich foods.

They found that:

"C3G increased energy expenditure, limited weight gain, maintained glucose homeostasis, reversed hepatic steatosis, improved cold tolerance, and enhanced BAT activity in obese db/db mice. C3G also induces brown-like adipocytes (beige) formation in subcutaneous white adipose tissue (sWAT) of db/db mice model. We also found that C3G potently regulates the transcription of uncoupling protein 1 (UCP1) both in BAT and sWAT through increasing mitochondrial number and function."

They conclude:

"Our results suggest that C3G plays a role in regulating systemic energy balance, which may have potential therapeutic implications for the prevention and control of obesity."

It should come as no surprise that berries and other anthocyanin-rich foods boost BAT given how many other known health-promoting interventions have been shown to also increase BAT. 

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

• Cold exposure - by far the best BAT inducer/activator
• Spicy / pungent foods, herbs & supplements - capsaicin / chilli peppers, curcumin / turmeric root, menthol/mint/camphor, oregano, cloves, mustard, horseradish/wasabi, garlic, onions
• Sulforaphane-rich foods - Broccoli, brussels sprouts, cabbage
•  Anthocyanin-rich foods - Blackberries, cherries, blueberries, raspberries, plums 
• Nitrate-rich foods - beets, celery, arugula, and spinach
• Arginine-rich foods - Good vegan sources include seeds (esp. sesame, sunflower & pumpkin), nuts (esp. almonds and walnuts) and legumes (esp. soy, lupin & fava beans and peas)
• Citrulline-rich foods - Highest by far in watermelon, but also some in onions, garlic, onions, cucumber, other melons & gourds, walnuts, peanuts, almonds, cocoa, chickpeas
• Luteolin-rich foods - Herbs (thyme, parsley, oregano, peppermint, rosemary), hot peppers, citrus fruit, celery, beets, spinach, cruciferous veggies, olive oil, carrots. 
• Rutin-rich foods - Buckwheat, apple peels, citrus fruit, mulberries, aronia berries, cranberries, peaches, rooibos tea, amaranth leaves, figs
• Healthy Fats - DHA / EPA / fish-oil, MUFA-rich diet,  Extra Virgin Olive Oil
• Fiber - Especially cereal fiber (wheat and oat fiber)
• Olive Polyphenols - Extra Virgin Olive Oil / Olive Leaf Extract / Olive Leaf Tea
• Other foods - Apples / apple peels / ursolic acid; Citrus fruit / citrus peels / limonene; Honey / chrysin
• Beverages - green tea, roasted coffee, red wine, cacao beans / chocolate
• Low gluten diet
• Methionine restriction - Reduce animal protein. Soy is low in methionine and high in arginine, but also high in leucine.
• Leucine restriction - Reduce animals protein. Leucine is highest in beef, fish, eggs, cheese and soy.
• Low protein diet
• Drugs / Supplements - metformin, berberine, caffeine, creatine, nicotinamide riboside (NAD), resveratrol, melatonin
• Medicinal Herbs - ginger root, ginseng, cannabidiol / hemp oil / medicinal marijuana, balloon flower root (Platycodon Grandiflorus)
• Time Restricted Feeding - most calories at breakfast
• Exercise & elevated lactate / lactic acid
• Acupuncture - locations Zusanli (foot - ST36) and Neiting (lower leg - ST44) 
• Whole body vibration therapy
• Avoid obesity/overweight
• Low testosterone / castration in mice (and men?)
• [being naturally thin - high metabolic rate]
• [being younger]
• [being female]
• [Ethnicity - having cold-climate ancestors]
• [being of genotype TT for rs1800592, TT for FTO SNP rs1421085 and AA for rs4994 as reported by 23andMe]

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

[1] Mol Nutr Food Res. 2017 Nov;61(11). doi: 10.1002/mnfr.201700261. Epub 2017 Aug 28.

Cyanidin-3-glucoside increases whole body energy metabolism by upregulating brown adipose tissue mitochondrial function.

You Y(1)(2)(3), Yuan X(4), Liu X(5)(6)(7), Liang C(2)(8), Meng M(5), Huang Y(5)(6), Han X(2), Guo J(2), Guo Y(2), Ren C(2), Zhang Q(2), Sun X(2), Ma T(2)(9), Liu G(3), Jin W(5)(6), Huang W(1)(2), Zhan J(1)(2). 

SCOPE: Obesity develops when energy intake exceeds energy expenditure. Promoting brown adipose tissue (BAT) formation and function increases energy expenditure and may protect against obesity. Cyanidin-3-glucoside (C3G) is an anthocyanin compound that occurs naturally in many fruits and vegetables. In this study, we investigated the effect and mechanism of C3G on the prevention of obesity. METHODS AND RESULTS: Db/db mice received C3G dissolved in drinking water for 16 wk; drinking water served as the vehicle treatment. The total body weight, energy intake, metabolic rate, and physical activity were measured. The lipid droplets, gene expression and protein expression were evaluated by histochemical staining, real-time PCR, and western blots. We found that C3G increased energy expenditure, limited weight gain, maintained glucose homeostasis, reversed hepatic steatosis, improved cold tolerance, and enhanced BAT activity in obese db/db mice. C3G also induces brown-like adipocytes (beige) formation in subcutaneous white adipose tissue (sWAT) of db/db mice model. We also found that C3G potently regulates the transcription of uncoupling protein 1 (UCP1) both in BAT and sWAT through increasing mitochondrial number and function. CONCLUSION: Our results suggest that C3G plays a role in regulating systemic energy balance, which may have potential therapeutic implications for the prevention and control of obesity.

© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

DOI: 10.1002/mnfr.201700261

PMID: 28691397

[Gordo]

Quote

 Here is a full list of the most C3G-rich foods.

Wow, black elderberries are impressive!

[Sibiriak]

A couple of years ago I posted some info on the blue honeysuckle berry ( Lonicera caerulea, aka haskap) found in Siberia (жимолость), Japan, Canada and elsewhere, but the search engine isn't  turning up the post.

In Siberia the blue honeysuckle has a great reputation for promoting health and longevity  and has a distinctly bitter element in the taste compared  to blackcurrants, for example.  (Canadian growers aim at cultivating less bitter varieties.)  The berries are extremely rich in  anthocyanins,  particularly cyanidin-3-O-glucoside.  

The potential health benefits of haskap (Lonicera caerulea L.): Role of cyanidin-3-O-glucoside   (May 2018)

https://www.researchgate.net/publication/324017444_The_potential_health_benefits_of_haskap_Lonicera_caerulea_L_Role_of_cyanidin-3-O-glucoside

 

Evaluation and comparison of nutritional quality and bioactive compounds of berryfruits from Lonicera caerulea, Ribes L species [blackurrant] and Rubus idaeus [raspberry] grown in Russia (2011)

https://pdfs.semanticscholar.org/7d9d/579dd8f18a52bd26ac2b2c1bdd434ba26a74.pdf

 

[Dean Pomerleau]

Cold Exposure Boosts Adult Neurogenesis

Over on this thread I referenced how cold exposure can increase mTOR activity in a good way to boost the immune system, bone health and maybe even brain health (but probably not muscle mass).

It does this not via the usual (pro-aging) mTOR pathway:

        Insulin/IGF -1  → AKT → mTORC1 → Anabolic effects

But via the alternative pathway:

        Cold → Norepinephrine → PKA → mTORC1 → Anabolic effects

Evidence for the immune and bone boosting benefits of cold exposure have been well established previously in this thread, while the brain benefits less so. So I did a search for recent evidence on the brain benefits of cold exposure and found this very recent gem [1].

It found that housing ad-lib fed mice at 42F (6C) for either 1 or 4 weeks triggered dramatically higher rate of new neuron creation in the hippocampus compared to ad-lib fed mice housed at room temperature (P < 0.01), as illustrated by the tall second bar in the graph below which shows the number of cells with a marker for neurogenesis in the hippocampal dendate gyrus (DG) in cold exposed (Cold1W - grey bar) vs. control (CON Cold1W - black bar) mice:

Cold exposure for 1-4 weeks also boosted expression of a bunch of genes associated with synaptic plasticity and synaptogenesis, including the well-known gene associated with brain health, BDNF, as shown here:

Interestingly, these brain benefits of cold exposure appear to be a result of cold exposure influencing the brain directly (likely via the above referenced pathway to increased mTORC1 activity in the brain) rather than as result of general metabolic improvements downstream of increased brown/beige fat in the periphery. They showed this by injecting another group of mice for one week with CL 316,243, which sensitized peripheral beta-adrenergic receptors and thereby boosts peripheral brown/beige fat but which doesn't cross the blood-brain barrier. These mice generated more brown/beige fat and weighed a little less than controls (just like the cold-exposed mice), but didn't exhibit any increase in neurogenesis in the brain relative to the control mice housed at room temperature (as illustrated in the second two bars of the first graph).

While there have been hints of brain benefits of cold exposure that I've alluded to previously, this new study provides the strongest evidence yet that cold exposure boosts brain health, at least in mice.

--Dean

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

[1] Front Neurosci. 2019 Mar 5;13:92. doi: 10.3389/fnins.2019.00092. eCollection 2019. 

Adult Hippocampal Neurogenesis Can Be Enhanced by Cold Challenge Independently From Beigeing Effects.

Kim JW(1), Han KR(1), Kim W(1), Jung HY(1), Nam SM(2), Yoo DY(3), Hwang IK(1)(4), Seong JK(1)(4), Yoon YS(1)(4). 

Free full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6411820/

In this study, we investigated the effects of cold challenge on adult hippocampal neurogenesis (AHN) and hippocampal gene expression and whether these are mediated by beigeing of peripheral fat tissues. Cold challenge (6 ± 2°C) for 1 and 4 weeks was found to induce beigeing effects in inguinal white adipose tissue based on hematoxylin and eosin staining as well as uncoupled protein-1 immunohistochemical staining. In the hippocampus, cold challenge for 1 or 4 weeks increased dentate gyrus neurogenesis and expression of genes related to AHN, including notch signaling, G protein-coupled receptor signaling, and adrenergic beta receptor-1. However, this enhancement of neurogenesis and gene expression by cold challenge was not shown by administration of CL 316,243, which induces peripheral beigeing similar to cold challenge but does not cross the blood-brain barrier. These results suggest that cold challenge promotes AHN and central expression of AHN-related, signaling, and β1-adrenergic receptors genes, and that peripheral beigeing by itself is not sufficient to mediate these effects. Considering the increase in AHN and gene expression changes, cold challenge may offer a novel approach to hippocampal modulation.

DOI: 10.3389/fnins.2019.00092 PMCID: PMC6411820 PMID: 30890905

[Dean Pomerleau]

Al posted this study [1] (thanks Al!), the latest in a long series on the effects of different levels of calorie restriction on mice. Previously the same authors (including John Speakman who spoke at our last CR Society conference) showed that mice on CR and housed at normal room temperature (which is cold for mice) preferentially retain brown adipose tissue (BAT) relative to other deposits of white fat, and comparable to the sparing of other organs critical to survival, like kidneys [2].

Not surprisingly, in this paper the authors found that mediators of BAT activity, particularly norepinephrine, are elevated cold-housed, CR'ed mice. The authors discuss why this might be the case, with an argument very similar to the one I made about the co-evolution of the CR and CE responses.  They say:

"Mice undergoing CR need to maximize conservation of energy, and low body temperature may facilitate this. However, to maximize foraging potential, and thereby increase calorie intake, BAT activation may be used. ... We can infer, however, that due to the effect of CR on body temperature and FAA that thermogenesis plays a part in this acute temperature increase. From an evolutionary standpoint, this is consistent, as animals undergoing times of food shortage would need to conserve energy during the day, but be able to become active quickly to spend as much time foraging as possible during the night. Stimulation of acute thermogenesis may provide lasting beneficial effects in these animals, including those that increase longevity, such as clearance of lipids and glucose from the blood and increased antioxidant defense. Importantly, these effects were seen after only 3 months of CR, which indicating remodeling of BAT metabolism occurs rapidly on food restriction. In addition, body mass in these mice stabilized after approximately 30 days [2]. Therefore, though BAT was used to an extent [i.e. burned during CR-induced weight loss - DP], over half of the BAT was conserved even at the highest level of restriction. This indicates an important role for thermogenesis in restricted [and cold-housed - DP] mice. Owing to the relationship between BAT, glucose, insulin, and lipids, this work could have implications for the relief of metabolic disorders far beyond diabetes, including atherosclerosis and cardiovascular disease."

They conclude with this diagram showing the synergistic effects of CR and CE. The red bubble in the diagram labelled "increase in norepinephrine and serotonin" shows no incoming arrow, but should have an arrow coming from a bubble called 'cold exposure".

--Dean

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

[1] J Gerontol A Biol Sci Med Sci. 2019 Apr 9. pii: glz023. doi: 10.1093/gerona/glz023. 

The Effects of Graded Levels of Calorie Restriction: XIV. Global Metabolomics Screen Reveals Brown Adipose Tissue Changes in Amino Acids, Catecholamines, and Antioxidants After Short-Term Restriction in C57BL/6 Mice.

Green CL(1), Mitchell SE(1), Derous D(1), Wang Y(2), Chen L(3), Han JJ(4), Promislow DEL(5), Lusseau D(1), Douglas A(1), Speakman JR(1)(2).

Animals undergoing calorie restriction (CR) often lower their body temperature to conserve energy. Brown adipose tissue (BAT) is stimulated through norepinephrine when rapid heat production is needed, as it is highly metabolically active due to the uncoupling of the electron transport chain from ATP synthesis. To better understand how BAT metabolism changes with CR, we used metabolomics to identify 883 metabolites that were significantly differentially expressed in the BAT of C57BL/6 mice, fed graded CR (10%, 20%, 30%, and 40% CR relative to their individual baseline intake), compared with mice fed ad libitum (AL) for 12 hours a day. Pathway analysis revealed that graded CR had an impact on the TCA cycle and fatty acid degradation. In addition, an increase in nucleic acids and catecholamine pathways was seen with graded CR in the BAT metabolome. We saw increases in antioxidants with CR, suggesting a beneficial effect of mitochondrial uncoupling. Importantly, the instigator of BAT activation, norepinephrine, was increased with CR, whereas its precursors l-tyrosine and dopamine were decreased, indicating a shift of metabolites through the activation pathway. Several of these key changes were correlated with food anticipatory activity and body temperature, indicating BAT activation may be driven by responses to hunger. 

The Author(s) 2019. Published by Oxford University Press on behalf of The Gerontological Society of America.

DOI: 10.1093/gerona/glz023

PMID: 31220223

----------

[2]  Oncotarget. 2015 Jun 30;6(18):15902-30. 

The effects of graded levels of calorie restriction: I. impact of short term calorie and protein restriction on body composition in the C57BL/6 mouse. Mitchell SE(1), Tang Z(1), Kerbois C(1), Delville C(1), Konstantopedos P(1), Bruel A(1), Derous D(1), Green C(1), Aspden RM(2), Goodyear SR(2), Chen L(3), Han JJ(4), Wang Y(5), Promislow DE(6), Lusseau D(1), Douglas A(1), Speakman JR(1)(5). 

Faced with reduced levels of food, animals must adjust to the consequences of the shortfall in energy. We explored how C57BL/6 mice withdrew energy from different body tissues during three months of food restriction at graded levels up to 40% (calorie restriction: CR). We compared this to the response to equivalent levels of protein restriction (PR) without a shortfall in calories. Under CR there was a dynamic change in body mass over 30 days and thereafter it stabilized. The time to reach stability was independent of the level of restriction. At the end of three months whole body dissections revealed differential utilization of the different tissues. Adipose tissue depots were the most significantly utilized tissue, and provided 55.8 to 60.9% of the total released energy. In comparison, reductions in the sizes of structural tissues contributed between 29.8 and 38.7% of the energy. The balance was made up by relatively small changes in the vital organs. The components of the alimentary tract grew slightly under restriction, particularly the stomach, and this was associated with a parallel increase in assimilation efficiency of the food (averaging 1.73%). None of the changes under CR were recapitulated by equivalent levels of PR.

DOI: 10.18632/oncotarget.4142

PMCID: PMC4599246

PMID: 26079539

[Dean Pomerleau]

The popular press is abuzz with a new article about the  benefits of coffee for weight loss via activation of brown fat (BAT). The actual study [1] has little to do with coffee per se, but focused on the effects of caffeine on brown fat, both in vitro and in vivo. 

The authors found that bathing immature mouse or human fat cells in caffeine increased markers of browning and thermogenesis. More interestingly, they found that within 30min of drinking a room-temperature instant coffee beverage with 65mg of caffeine there was a significant increase in the temperature in the shoulder region of human subjects where BAT deposits are known to be located, when compared to the same subjects response to drinking room-temperature water. Here are the graphs and thermal images before and after the coffee beverage:

As you can see, the increase in temperature on either side of the neck is pretty striking.

This isn't the first time that I've discussed caffeine as a method of boosting brown/beige fat. But this appears to be the most direct evidence to date that modest levels of caffeine intake can induce BAT-mediated thermogenesis in humans, even in the absence of cold exposure.

This could potential explain, at least in part, the mounting evidence that coffee and caffeine intake are associated with lower rates of diabetes [2]. 

--Dean

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

[1] Scientific Reports volume 9, Article number: 9104 (2019) 

Caffeine exposure induces browning features in adipose tissue in vitro and in vivo

Ksenija Velickovic, Declan Wayne, Hilda Anaid Lugo Leija, Ian Bloor, David E. Morris, James Law, Helen Budge, Harold Sacks, Michael E. Symonds & Virginie Sottile 

Abstract
Brown adipose tissue (BAT) is able to rapidly generate heat and metabolise macronutrients, such as glucose and lipids, through activation of mitochondrial uncoupling protein 1 (UCP1). Diet can modulate UCP1 function but the capacity of individual nutrients to promote the abundance and activity of UCP1 is not well established. Caffeine consumption has been associated with loss of body weight and increased energy expenditure, but whether it can activate UCP1 is unknown. This study examined the effect of caffeine on BAT thermogenesis in vitro and in vivo. Stem cell-derived adipocytes exposed to caffeine (1 mM) showed increased UCP1 protein abundance and cell metabolism with enhanced oxygen consumption and proton leak. These functional responses were associated with browning-like structural changes in mitochondrial and lipid droplet content. Caffeine also increased peroxisome proliferator-activated receptor gamma coactivator 1-alpha expression and mitochondrial biogenesis, together with a number of BAT selective and beige gene markers. In vivo, drinking coffee (but not water) stimulated the temperature of the supraclavicular region, which co-locates to the main region of BAT in adult humans, and is indicative of thermogenesis. Taken together, these results demonstrate that caffeine can promote BAT function at thermoneutrality and may have the potential to be used therapeutically in adult human.

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

[2] Eur J Nutr. 2016 Jun;55(4):1345-58. doi: 10.1007/s00394-016-1206-0. Epub 2016 Mar 30. 

Coffee consumption, obesity and type 2 diabetes: a mini-review.

Santos RM(1), Lima DR(2).

PURPOSE: The effects of regular coffee intake on weight gain and development of diabetes are reviewed. The pathophysiology of obesity and type 2 diabetes as well as the necessity of preventive options based on the increasing prevalence of these two disorders worldwide is briefly discussed. The relationship between weight gain and development of diabetes is also presented. The two major constituents in the brewed coffee, chlorogenic acids and caffeine, are responsible for many of the beneficial effects suggested by numerous epidemiological studies of coffee consumption and the development of diabetes. METHODS: A wide search of various databases, such as PubMed and Google Scholar, preceded the writing of this manuscript, focusing on key words that are part of the title. It was selected mainly review papers from in vivo, ex vivo, in vitro experimental studies in animals and human tissues as well as wide population-based epidemiological studies in the last 10 years. CONCLUSION: As of today, there are mounting evidences of the reduced risk of developing type 2 diabetes by regular coffee drinkers of 3-4 cups a day. The effects are likely due to the presence of chlorogenic acids and caffeine, the two constituents of coffee in higher concentration after the roasting process.

DOI: 10.1007/s00394-016-1206-0

PMID: 27026242 

[mccoy]

Has anyone of you guys ever experienced the effects of BAT activation (localized heat, and so on...)? 

[Dean Pomerleau]

51 minutes ago, mccoy said:

Has anyone of you guys ever experienced the effects of BAT activation (localized heat, and so on...)? 

The answer is yes, with the cautionary note that a placebo effect is hard to rule out when it comes to the feeling of BAT kicking in. More objectively, it appears both Gordo and I have experienced a significant improvement in glucose clearance, although that too is hard to quantify/prove.

See this post by me and the following one by Gordo.

--Dean