Mitochondrial Anarchy: A case of BAT attack

He’s back.  Well, actually I never went anywhere, but it’s been a few months since I added to the blog.  In the mean time hundreds of pounds were lost by people I worked with directly, an invited commentary was submitted to a journal, and I have performed dozens of calorimetry, blood sugar, and food experiments.

Sometimes it’s necessary to isolate from all the bias and do the boring thinking part.  It’s far easier to hype, but at the root of all innovations is a break from status quo.  Like trucks drafting on the highway, it’s quite easy to get sucked into the popular dogma to avoid slamming into the guardrails.

My mentor in innovation, aviation rebel Burt Rutan, says you have to have “confidence in nonsense” to innovate.  That doesn’t mean that every nonsensical idea represents brilliance, but there is a certain break with the masses that occurs with each innovation.  In addition to crazy ideas (we can find a lot of those out there), one must measure carefully and that is the boring part, but I LOVE it. I also like old books, because they give one a much more grounded view of how our current ideas evolved and sometimes it’s easier to see the forks in the road that lead to the current (obviously wrong) idea about eating by stepping back and working your way through it.  If you love history and musty, stained books, then it’s really a joy to do it.

History not reflected, repeats.

There’s been a lot of ground covered in the nearly three years I have been blogging and it’s exciting just how much more research is coming out every year. So many people are doing great work.  I have much more on metabolism and the macronutrient shuffle, but I’d like to cover some new work that published over the last year and a few papers have been meaning to cover for some time.

Since it’s been a while since I last posted (yikes!) or you are visiting for the first time, let’s digest a few bits before going into the main topic. What I want you to know at the highest level is food, or fuel, is THE reason people fight obesity and many chronic diseases.  Further, I think macronutrient labels (protein, carbohydrate and fat) are  meaningless when discussing food, eating schemes or meals.  Exercise is incredibly beneficial with increasing performance and many health biomarkers, but it’s not the fastest way to lose body fat and can significantly impede weight loss.

Your metabolism isn’t broken or low – in fact it scales (gets larger), as does lean mass, with weight.  Hitting the gym to put on lean mass to burn calories and ramp the metabolism isn’t necessarily the solution.  If lean mass was the only thing needed to lose weight then why do bodybuilders or football players ever get fat? They certainly both have more lean mass than I or Aunt ethel will ever have. You know what?

You can’t out exercise your mouth.

It’s food. It is what they eat not how they burn it.  I didn’t say don’t go to the gym nor am I attacking bodybuilding or football, but I want to disconnect those activities from the notion that people are overweight because they aren’t “active” enough or don’t have enough “lean mass” to melt the fat away. It simply isn’t true and for the most part, exercise nowhere near as an effective way to lose weight as diet – especially for people with 50+ lbs to lose.  I am  not implying that there aren’t ways to boost metabolism, but what your diet has a much larger effect on the outcome.

For the last year,  I  had the luxury of measuring  many situations and conditions in a home metabolic lab. There is a seemingly unending list of myths I once believed, things that are repeated as fact in everyday conversation, which are not consistent with what I see in the lab or the peer reviewed literature.  It’s humbling and frustrating all at the same time.  Some of you see this and many more don’t, but anyone that carefully measures would come to similar conclusions. Part of the problem is the monolithic, group-think that seems to infect the fitness/diet community. Certainly the medical community isn’t immune.   I was as guilty as the next.

I’ve heard it said that a generalist is one that knows less and less about more and more until they know nothing about everything and a specialist is one that that knows more and more about less and less until they know everything about nothing. We have a lot of generalists and specialists parading dogma despite unprecedented understanding about how our body works.   I’ve reflected a bit on just how this happens and perhaps we can use it as a sub theme for today’s post.

In the northern hemisphere it is fall, and this is now ABSOLUTELY one of my favorite times of the year.  This is biologically a period  running up to winter’s conservation.  It’s a time when our metabolic system becomes stressed and will rebound with vigor in the spring. This is analogous to muscle hypertrophy in response to the biological stress of lifting a weight.  The overall endocrine system is not stressed by excessive nutrition; it’s stressed by caloric restriction and there is 70 years of data to support this hypothesis.

Every organism tested, from yeast to mammals, lives longer (40-50%) when Calories are restricted typically ~15-30% (up to 25-60%)  of normal for that species (1-3).  The ideal notion is to supply sufficient nutrition with minimum Calories.  Note: you don’t get life bonus points and extra Calories to eat by purposefully concentrating biologically active compounds [insert supplements] and ingesting them in huge doses not found in nature – health doesn’t come in a pill or powder. Chronic overnutrition isn’t solved with more food or nutrients. For over 150 years nutrient content is the catch-all buzz to market excess food.

This idea of Calorie restriction should invoke a similar curiosity in everyone:  if one continually restricts calories by 15-30% of normal, shouldn’t  a point of diminishing return eventually be reached?  In other words, if  a certain number of calories are “necessary” to maintain a person or organism, restriction below that number for a lifetime should  eventually catch up.  Can one truly be in “deficit” forever? Let’s not ask politicians; after all Lavoisier got decapitated for meddling in such political nonsense.  It’s still an interesting question: how much is enough food?

Creating Permanent Change

Over the last 5 years I took a decidedly different approach to the problem from the proceeding 20+ years of relative “failure;” I couldn’t control my weight and had biomarkers inching in the wrong direction.  Looking back now, especially after spending the last few months on a journal manuscript, countless self-experiments, and coaching dozens to success, I can summarize my perspective by offering  a simple shift in two questions that drove all of this work.

1) How do I lose weight -> Why do I gain weight? 

2) What do I eat? -> How is the food I eat processed?

While these might appear to be nearly identical questions, it turns out they are extremely different questions and the answers cause conflicts with many popular “schemes” about food and metabolism.  With that, let’s segue to one area of metabolism you absolutely can have a dramatic impact on even at the cellular level.

Power Plants and Fuel

We all know that in order for an engine to run an oxidizer and fuel must be supplied. The reaction creates new products and typically a lot of extra heat.  When the Space Shuttle Main Engine used to fire, hydrogen (fuel) and oxygen (oxidizer) were combined to make water and obvious extra heat.

The hydrogen and oxygen fuel/oxidizer were contained in the large External Tank in the center.  The solid rocket boosters (on each side of the ET) used Aluminum for fuel and ammonium perchlorate for oxidizer. I think it is fascinating to think that the same basic chemistry of a rocket engine is used by the power plant of cells, the mitochondrion, deliver energy to live and move.

Instead of rocket fuel, hydrogen, mitochondria use amino acids, monosaccharides, fats, and alcohol for fuel. Combined  with atmospheric oxygen, they oxidizer,  they produces ATP + waste heat.  The waste heat is managed and that is what maintains our temperature – we are designed to live in environments cooler than body temperature in order to dissipate this excess heat.  ATP is the currency of energy in the cell and you can learn more if you want in this tutorial at Kahn Academy.

I am only dealing with FAT/CHO in the graphic, because ultimately the fate of the other macronutrients (amino acids/alcohol) end up inserting into the CHO pathway.  Later we’ll clear up some of the many myths of ingested versus endogenous sources, but suffice it to say one doesn’t store alcohol (in coolers doesn’t count).  Breaking down of tissues for either indispensable amino acid stores or back up energy is not as common as portrayed as it is easily avoided with even modest amounts of ingested whole-food Calorie.

So we have a fuel currency and everyone wants to believe the obesity “problem” is a simple macronutrient ratio. We hear it’s fat. No, it’s protein. No, it’s carbohydrate.   The  truth is that we all simply “eat” too much. Chronic overnutrition is THE problem, because  in the real world, Calories are scarce.  That is why I find the mitochondrion and mild cold stress so fascinating.  These are inextricably linked and our biology has provided a way to not only recycle that waste engine heat, much like the heater in your car, but in certain situations stop producing ATP altogether and just create heat.

What is even more fascinating is that while BAT seems to get the center stage in the press, every mitochondrion in your body has the ability to play in this ATP/heat exchange. It turns out that mitochondria even have their own DNA – separate from the genes that make you, “you.”  In the last few years, scientist have been toying on the edge of some incredible work that addresses a certain mitochondrial DNA diseases (4), and  you can explore that more  here and here.   I’m not thinking about jumping into mitochondrial DNA modifications at the moment, but it is important to ponder just how independent these tiny power plants are and consider the overall coordination involved in them working in unity.

With the exception of red blood cells,  all your cells contain these powerplants and they are not only at the center of this waste heat production I’m always tapping into, but also at the very root of aging.   What seems paradoxical is that caloric restriction actually increases mitochondrial biogenesis (formation of new mitochondrion); that’s  more power plants created on a diet of less fuel.  Overall, the point to keep in mind is that each mitochondrion decides: 1) what fuel to use based on a host of coordinated signalling, 2) whether or not to produce ATP, and 3) is capable of generating an enormous amount of heat.

Record Breaking Wisdom

A little over a  week ago Wim Hof broke  another world record – one hour and 53 minutes in direct contact with ice.  He’s demonstrated numerous time this ability and although it’s been shown that he can generate up to 5 times the amount of heat of younger, healthy (untrained men) he would be the first to humbly say, anyone can do this.   He in fact has trained many people to adapt to mild cold stress and today we will look at science that backs up his claims.

There are numerous other medical benefits, but let’s move beyond. I think it is funny to note that when I visited him last during a Netherlands winter, he always reached for a jacket when we went for walks or to the grocery store and we laughed at the fact I just threw on a pair of gloves and a hat. The iceman has a coat.

Now, I am not trying to imply I can take him on in dueling cold, but wish to point out we all have these habits.  Today, I will give you a few things to change as winter approaches that will tweak these habits and help you adapt. Back to mitochondrial response to cold shock.  The first thing to recognize is that these responses happen at the cellular level.  Each cell is it’s own little domain, and although coordinated and affected by overall endocrine activity, they have the power to bypass ATP production in defense of cold shock (5).  Next is to understand that heat generation not limited to the mitochondria in BAT. Every mitochondrion contributes via the normal cellular activity resulting in  80% waste heat, but further, they can all take it up a notch and give us the the extra 20% in heat instead of ATP.

Adapting the cool approach

In 2008, researchers demonstrated that muscle cells also contribute significantly to adaptive thermogenesis. (6). In this study 11 lean men were tested at 22C and 16C inside a respiration chamber (a whole room indirect caloriemeter).  Even though activity actually fell during the period of mild cold stress, total daily energy expenditure (TDEE) increased.  After a baseline measurement of 34 hours at 22C, they were measured for 84 hours at 16C (60F).  This temperature was picked so as to not induce shivering.

Qualitatively, it happens to be exactly the temperature I find that the most people can tolerate with little period of adaptation. A biopsy from  leg muscle (M. vastus lateralis), was taken after each test period and later analyzed for mitochondrial uncoupling.  Those results clearly demonstrate it is present.  The authors also note that epinephrine  has been reported to increase total body energy expenditure of up to 40%.   What this means is that whether you have BAT or not, you can still adapt and create non-shivering heat.  Not only that, but it’s more energetically favorable to skip the ATP step (shivering/exercise) and just dump the high-calorie stored fuel (FAT) directly to heat.

We learned in A New Eye on BAT, that Irisin produced in a response to exercise promoted the “browning” of white adipose tissue and caused them to join the Muscle/BAT heat game.   The puzzling paradox was that of a tissue encouraged to “waste” energy by producing heat as a response to increased activity.  At first, these two actions would appear to conflict: excess activity causes tissue to be formed, which in turn creates 100% waste heat instead of ATP involved in cellular activity and survival.   As examined from the larger perspective it seems like an energy death spiral, but if exercise is viewed as a modern day mimic of shivering, this is a more effective way to keep the body warm – i.e. it conserves energy.

Even though exercise and shivering are primarily an activity of high respiratory quotients (i.e. glycogen/CHO, not FAT), the body does have a system to efficiently adapt to a dense fuel source (FAT) without the deleterious tissue breakdown associated with prolonged/intense muscular activity. Earlier this year, two related  research projects showed up.

The first looked at the simple acclamation progression of exposing  subjects to an environment temperature of 15-16C (60F) for 10 consecutive days and then looked at the activity level of non shivering thermogenesis (NST) and BAT. (7)  At the same time they surveyed three key indicators of comfort:  How are you feeling (temperature) now? Do you think this is….(comfortable to uncomfortable)? and Are you shivering?

What is not too surprising is that after 10 days all of the questions saw a significant improvement (move towards comfort/non shivering). We’ll discuss this below. The acclimation also increased NST by 10%. Remember, this is heat generated directly through mitochondrial activity bypassing the shivering/ATP step.  While no rise in RMR was detected (I suspect they didn’t measure during cold exposure), they also don’t report RQ, so there’s no way to tell if an increase in fat oxidation was associated with the acclimation. They do state that the mitochondria became sensitive to fatty acids with the exposure. The also briefly discuss the lack of skeletal muscle recruitment seen in earlier studies by same team (above), but suggest it might be linked to intermittent exposure vs the previous continuous exposure.

Finally, It was interesting that BAT was detected in 94% of participants before and 100% afterwards – a long way from just  decade or so ago when it was believed we lost all BAT by adulthood.   Overall the detectable BAT quantities increase by 37%.  And let’s go back to the test conditions…we are talking about 60F (15C) for only 6 hours a day!  This is a great fall/spring day whether you happen to now be in the Northern/Southern hemisphere.  This is NOT cold…nor is it an ice bath or extreme.  It’s the equivalent of spending a couple of hours in cool, not cold conditions. This is something everyone could easily accomplish.

Spice it up.

The second paper was from a team in Japan and looked at 2-hour mild cold stress (17C/62F) treatments for six weeks, 19C/66F 2-hour exposure on energy expenditure (EE), and compared these to daily ingestion of capsinoids (pepper extracts) for six weeks. (8)  Similar to the study above, a clear association of mild cold stress and increased metabolic activity was demonstrated.

In this study of 51 young men, a little over half showed BAT that was activated by the one time exposure to 19C (see Figure 1, E). Of the detected/undetected, both saw a significant increase in EE (c), but those with BAT saw 252 kcal/day vs 78.8 kcal/day. They also saw a strong association between fat-free mass and EE – in other words resting metabolic rate scaled with fat free mass.

Reflecting back on our  Part 3 of Muscling Your Metabolism,  don’t forget that lean mass scales with weight – ladies (and men), pay attention here – the more you weigh the more lean mass is under the “fat suit” to carry around those extra pounds and the higher your metabolism is to support such effort. (9) At the same time let’s also not forget that it’s also been demonstrated that the average daily energy expenditure of traditional hunter gatherers was no different than that of modern day Western (US and European) counterparts after controlling for body size; as such, “lifestyle had no effect on total energy expenditure.” (10)

So let’s look at this clearly, and accurately, in terms of my simple question above: if putting lean mass on to burn calories (clearly demonstrated in this and other studies) was our main concern, then the bigger you are the more lean mass you have and the higher the metabolic rate.

Further, if we are all just suffering from too much sedentary lifestyle and just need to go roll more boulders and chase a few antelope, then this isn’t very consistent. Your metabolism or lean mass is likely not the problem at all and that’s why one can continue to run marathons and not lose weight.   We eat too often, too calorie dense and too much.

Spread the word: you can’t out exercise your mouth. 

Now, back to the mild cold stress. What is also interesting in a cohort of similarly aged young men that fat-free mass was closely tied to EE at 27C, but not at 19C during mild cold stress (see: F-H). So this clearly distinguishes between BAT contribution to EE vs fat-free mass.  But like the study above, the 6-week, 2-hour a day exposure to 17C/60F resulted in an increase  in both BAT activity and BAT detection: individuals with no BAT detectable at the start showed active BAT at week 6 (see Figure 2A in the paper).

Obviously anyone paying attention here should see the conflict, maybe in these short term acclimation studies (intermittent) BAT becomes the first line of defense (if you have it). Further, if you don’t have BAT it seems that one can recruit it. Finally, there are also examples that even skeletal muscle can contribute in chronically cold (read natural winter exposure pre modern world).  We’ll address this in the practicum below.

Finally, this study had this interesting twist of the effect of capsinoids from a specific pepper (do you hear the supplement companies beating your door down?).  This is actually an interesting class of non-pungent capsaicin from a sweet pepper (CH-19 Sweet, Capsicum anuum L.).  Reasoning that the increase in dietary induced thermogenesis was related metabolically to the heat rush stimulated by pepper exposure, they tested in a cross-over, randomized, single-blind trial comparing placebo/capsinoid capsules ingested daily for 4-6 weeks… and it worked!

Those receiving the capsiate had an increase in EE similar to the same treatment with mild cold stress.

That’s actually surprising and an interesting result.  Once again, they didn’t report the more important figure, RQ, which would tell us how much more of this EE activity is actually helping contribute disposal of stored fat.  I have first hand data that the cold exposure does decrease RQ over time (moving towards more fat metabolism).   It would be interesting to see if that played out here as well.

The Practicum – Your Autumn Experience

Ok, so we moved all over the place today and I am always asked for practical applications of all of these intellectual curiosities.  With a few extreme exceptions, the move-more message to burn fat and increase metabolism is pretty weak at best.  Further, the lean muscle burns fat argument, while true, is mostly irrelevant.  What you put in your mouth (future post) every day has far more effect on your results if fat-loss is the goal. If you want to run faster, jump higher and swim farther – exercise is the solution.  Wim is challenging the endurance portion of exercise, but that’s for another time.

This is not to say one can’t have a profound impact on metabolism with mild cold stress, but even that is not going to make up for the $1 buffet; you can’t out exercise your mouth.  The only exercise guaranteed to work is to isometrically clench one’s mouth in the presence of excess calories.  Let’s assume you’ve picked your dietary regime, be it paleo, vegan, body for life, whatever… and you want to lose.

Fall is an EXCELLENT time for the adaptation we see in all of these studies.  This is the natural period where cold ushered in and our bodies are designed to adapt – everyone can do it, don’t use the pathetic story of cold natured, big boned, or genetic destiny.  Instead, ease into it.

I have given out one prescription for muting your immediate response to cold and increasing your cold (and paradoxically hot) tolerance.  I call it: 10-20-10x and it is a procedure Wim Hof and I developed together based on both of our experiences.  First, you need only a GYMBOSS timer (you can contribute by getting it on my Amazon store or there is a free App) and a shower (consider the silicone skin for $2).

Finish the cleaning part of shower at a normal temperature (hint, slowly reduce your shower from scalding to normal-warm over a week or so if steaming shower is your thing).  Then you’ll do 10 seconds of warm followed by 20 seconds of cold and repeat that interval 10 times (10-20-10x).  You want to end on cold for a minute or two.   It will suck pretty bad at first, don’t say you weren’t warned.  That being said, it gets not only tolerable, but the best description I’ve heard is you’ll eventually get the same “runner’s high” after a race. It really gets you going.

What is going on during this crazy exercise?  Vasoconstriction/vasodilation is alternating and blood is pulsing to and from the extremities. Believe me you will feel it in your fingers, toes and scalp.  Ladies, I am told a cold water rinse with hair closes the cuticle and my South American female followers SWEAR this tightens the buns  and skin – I don’t know, but it’s a bonus if true.  What you will find is a very perceptible increase in mood and well being – this boosts the endorphins and gives a great morning rush.  It also will slowly mute your response to sudden cold, be it opening the shower door, the office door, or cool water.  Your body eventually doesn’t panic in the “fight or flight” sense to sudden cold exposure and that helps with overall comfort.

As well, I think this is superior to just cold showers if that’s already your thing. The constrict/dilate method is additionally a great way to alleviate  post workout soreness.  Here is the modification I would make: fill the tub with cold tap water before you do this and then sit in that after the 10-20-10x for 5-10 minutes – need to submerge farther for upper body workout.  Even without ice, you will see a significant difference in following and next day in soreness – even if you are just starting to exercise.

Glove before sweater, make you look better.

So this brings me to my final couple of observations. Don’t be afraid of cool temperatures.  I am not suggesting you go out and brave dangerous cold levels (0C/32F air and 16C/60F water are the lower limits in my book), but do the reverse of common layering with skiing – bring your layers WITH you and layer as necessary; don’t wear them and remove when too hot.  Are you really going to freeze walking from the house to the car…in the garage? What about from your parking space to the warm office building? How do we dress different in summer and winter when the environments we inhabit are virtually the same?

These small times of exposure both condition you and as we have seen today have real, measurable effects on your overall metabolic pathways. Drop the thermostat a bit – it doesn’t take extreme and you will get used to it. This isn’t extreme as I have been suggesting for a few years and we don’t need super-human feats of ice endurance, not even Wim believes this as the champion of champions on the subject. What I want everyone to do if you want to get in touch with the real biological self is expose yourself to the seasons, they matter.  If you live in an extremely mild climate, then invent them.

Remember, the only species that get sick and chronically ill are us and the pets we keep warm and fed: they get the same diseases and struggle with obesity. It’s not their little doggie/kittie treadmills and the amount of “protein” in their food – it’s chronic overnutrition.  Animals conserver and so did our ancestors, despite what your rope climbing, tire-tossing, five-toed shoe friends want to believe.   I see consistently .6-.8 lbs a day loss in my clients with no exercise. Sorry again for the long delay. I am sure there will be a lot of discussion.

I don’t want to debate diet at the moment, so let’s stick to the subject and be respectful – I am thrilled that our many comments have avoided the trash-talk elsewhere. Have you been doing contrast showers for a while? Let us know your experience?

As always, I’m not selling books, supplements, or bad ideas and I self-fund my research, so if you like this PLEASE donate and perhaps consider a regular contribution. It’s appreciated and all of it goes to my mid-life crisis metabolic lab, gadgets and historical textbooks.

 

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Thanks!

Ray

References

(1) Guarente, Leonard. “Mitochondria—a nexus for aging, calorie restriction, and sirtuins?.” Cell 132.2 (2008): 171-176.

(2) Haigis, Marcia C., and Leonard P. Guarente. “Mammalian sirtuins—emerging roles in physiology, aging, and calorie restriction.” Genes & development 20.21 (2006): 2913-2921.

(3) Koubova, Jana, and Leonard Guarente. “How does calorie restriction work?.” Genes & development 17.3 (2003): 313-321.

(4) Tachibana, Masahito, et al. “Mitochondrial gene replacement in primate offspring and embryonic stem cells.” Nature 461.7262 (2009): 367-372.

(5) Fujita, Jun. “Cold shock response in mammalian cells.” J Mol Microbiol Biotechnol 1.2 (1999): 243-255.

(6) Wijers, Sander LJ, et al. “Human skeletal muscle mitochondrial uncoupling is associated with cold induced adaptive thermogenesis.” PLoS One 3.3 (2008): e1777.

(7)  van der Lans, Anouk AJJ, et al. “Cold acclimation recruits human brown fat and increases nonshivering thermogenesis.” The Journal of clinical investigation 123.8 (2013): 3395.

(8) Yoneshiro, Takeshi, et al. “Recruited brown adipose tissue as an antiobesity agent in humans.” The Journal of clinical investigation 123.8 (2013): 3404.

(9) Prentice, Andrew M., et al. “High levels of energy expenditure in obese women.” British medical journal (Clinical research ed.) 292.6526 (1986): 983.

(10)  Pontzer, Herman, et al. “Hunter-gatherer energetics and human obesity.” Plos one 7.7 (2012): e40503.