Saturday, February 19, 2011

Basic Science - Energy is Everything

Let's review.  Some 9 months ago, an excitable young psychiatrist of reasonable pedigree launched Evolutionary Psychiatry as a means to explore how the differences between our modern lives and diets compared to traditional/evolutionary experiences may influence the generation of mental illness.  To that end she peeled back the edges of several lines of inquiry - what mental illnesses are increasing rapidly, and what are the theorized reasons as to why?  What are the correlations between mental illness and the known diseases of civilization (heart disease and type II diabetes, primarily, though acne, IBS, and autoimmune diseases of all kinds fall in that rubric)? What dietary factors are drastically different between the nutrient-rich traditional fare and our post-modern industrial food, and what is known about how those dietary factors affect neurotransmitters and brain energetics?  So I read, and read, and read, and depend upon a small cadre of loyal compatriots and commenters with a similar nose for research and a similar goal, and together we have uncovered some interesting things, and nowhere in thousands of pages of reading have I uncovered something that would absolutely refute my original hypothesis.

Part of the story of Evolutionary Psychiatry is the story of its creator and how she [I] thinks.  And when I say I have no patience for philosophy, I mean it.  I've rarely made it past the "God cannot be both benevolent and omnipotent" chapter one of most philosophy books before they are consigned to the dustiest reaches of the bookshelf.  I am left-handed, so theoretically more able to bring in the right brain (though in all likelihood I am also predominantly left-brained like most of you).  I am a woman, therefore likely more balanced between dopamine and serotonin in my ponderings.  I think in collages.  In pictures.  In stories.  My influences are literature and music, the oral and written histories of our people.  For some, the structured rationality of philosophical thought creates links and certainty.  For me, that structure is an imposing irritant and a distraction from the elusive creative links.  I hope I make up in scope for what I lack in rigor.  I rely on folks like Denise and Ned to lose themselves in numbers.  I want the story behind the numbers.

In Evolutionary Psychiatry there are only a few truths that bob to the surface again and again.  Inflammation is the mediator of most evils.   Energy should be made efficiently or there will be a cost.  Fatty meat is good.  Starch is not a dirty word, but an excess sugar certainly is. Ketosis in moderation can be a powerful tool.  Plant protein should be regarded with suspicion as an inflammatory mediator.  Stress and sugar and poor sleep damage the brain.  We should probably consume a little more dirt and get a little more sunshine

But let's bring it back to energy.  Energy is everything, and the brain, for all its small size, a massive consumer of energy.  Energy for eukaryotic cells is primarily made in the mitochondria. 

Image from The Science Experts

There are a few "need to knows" about mitochondria.  Like most engines, they create waste.  However, it seems that what we want is plenty of mitochondria working at full efficiency.  If we have leftover or damaged mitochondria just hanging out, they seem to create destructive reactive oxygen species and general mischief (1).  Mischief such as dementia, premature aging, cancer, and probably autism

Things that make mitochondria happy and promote effiency and clean energy:

1) A high-fat diet and utilization of ketones
2) A ready supply of energy and mitochondrial cofactors such as the animal flesh-derived carnitine, creatine, and carnosine, and the cholesterol buddy buddy ubiquinone (CoEnzymeQ10), vitamin A, and the football crew of B vitamins are also utilized in the respiratory chain.
3) Protein and/or calorie restriction which promotes the activation of PPAR (that is peroxisome-proliferator acttivated receptors).  See, the mitochondria have two major types of garbage containment facilities, the lysosomes and the peroxisomes.  They are the waste clean-up crew, and they become more active in states of protein restriction and ketosis.  In addition, the old and inefficient mitochondria spewing more reactive oxygen species than they ought get properly decomissioned in states of protein restriction and ketosis.  This is one part of a positive clean-up process called "autophagy." 
4) Aerobic exercise seems to stimulate the creation of new, shiny, efficient mitochondria (2).

What sorts of things promote mitochondrial ineffiency and general dirty cell-killing cancer dementia promoting badness?

1) Hyperglycemia
2) Inactivity
3) Micronutrient deficiencies
4) Never dipping into ketosis

I'm guessing the mitochondrial research folks probably never heard of the paleolithic or primal style approach to diet and living.  But the common recommendations of that approach all converge to make mitochondria mighty happy.  Even the paleo conservatives with their fat phobia will be low carb and encourage intermittent fasting - which in combination should bring *some* ketones into the picture along with temporary protein restriction to promote autophagy.  Paleo/traditional foodists will be rather strident in getting plenty of micronutrients and will have the steaming plates of offal to prove it.  The special mitochondrial-loving amino acids found in meat will be, more than likely, adequately consumed by the meat-loving paleo eater.  In addition, activity is encouraged, lots of it, in realistic exertion and quantity.  The diet itself, being antinflammatory and muscle-sparing, is the perfect fuel to spur activity.

In contrast, the Standard American Diet du jour will promote inflammation ultimately resulting in hyperglycemia, weight gain, inflammation, fatigue, and sedentary living.  Micronutrient deficiencies will be the rule, unless one is exceedingly careful.  And one is told never to let 3 hours or more go by without eating lest the metabolism sputter to a halt (which I'm ashamed to admit I ever believed).  Restricting calories to the point of avoiding obesity only while eating 5-6 times a day is no picnic.  Welcome constant food with constant hunger and constant restriction.  One could hardly think of a more unnatural way to eat, or a better way to make for miserable free-radical spewing mitochondria.

Yes, more research papers, more basic science, a deeper look at a vast picture, and more of the same old answers.  If you haven't given IF a try, consider skipping breakfast every once in a while.  Or at least have some stretches of time where fat is the primary macronutrient you consume (but avoid those vegetable oils, of course).  You might be surprised how you feel - not weak, but focused, energetic, and driven.  All the better to devise a plan to bring back that large ruminant to the camp for a delicious supper.  Yum.

(Thanks once more to Jamie who sent me several of the papers and links.)


  1. Nice post, Emily! Hits the high points nicely.

  2. Great post. In light of your comments on the benefits of ketosis (or at least ketones, maybe I'm confusing the two to some degree), what are your thoughts on Harris' recent blog posts regarding his statements that ketosis all the time may not be desireable?

  3. Dr Deans

    This is an excellent summary and a highly accessible one to forward to skeptics too! Thanks.

    I found your blog last week and commented on your bipolar thread. As it was sometime ago you posted it I've pasted here a link I found really fascinating in case you haven't seen my comment yet.

    'The One True Path' Jennifer Walsh

    It's probably one you've already come across. I just about got my ahead around the science (!)
    but it really highlighted for me the crucial aspect of insulin/IGF overload and how far reaching the effects can be.

  4. " excitable young psychiatrist of reasonable pedigree..." An excitable young English major has also created a bit of a stir this last year. Keep on stirring!

  5. I have been reading stacks of research papers on autophagy. My readings say that protein and calorie restriction alone will not bring on autophagy. You need low levels of insulin with no nutrition to fool the cells into thinking it is starving. That means total fasting.

    One exciting new paper I read is entitled " Short Term Fasting induces profound neuronal autophagy" by Alirezael, Kemball et all. The paper is behind a paywall at the Autophagy Journal. (I am a subscriber)

    The paper says it was believed that the brain was always protected from starvation so autophagy could never be forced. They proved that autophagy in the brain can be forced with fasting. They believe that intermittent fasting could be a cure or at least a prevention for many neurological diseases. Great stuff.

    I am 68 and have been on the paleo diet for two years and intermittent fasting for a year and a half. I personally do 16-20 hour total fasts twice a week. I believe my memory has now returned to youthful levels I enjoyed until I was 55.

  6. Thanks Paul

    Mark - I agree with Kurt (I find I differ with him more by style than substance). First off, chronic deep ketosis is a difficult state to achieve - given the protein and carb restriction required. In the case of epilepsy, very tight control of brain energetics is required. You will find the same with medication treatment of epilepsy - often doses will need to be multiple times a day, and some people can't even tolerate generic versions with somewhat different percentages of active metabolite and different dosing release systems than the brand names. So in epilepsy, a state of chronic ketosis (if it works) is likely the desired state. Now when you use the same medications as used in epilepsy for mood stabilization, the absolute level seems to be less important. So you can push the doses to all at bedtime, diminishing side effects and increasing compliance, for example. For many people there seems to be no clinical difference in mood stabilization. Now that may not be the fairest comparison - after all, we don't have any clinical trials, well done or not, of ketogenic diets for mood stabilization. But consider the ketogenic diet trial in autism - benefit was achieved with a 4 weeks on, 2 weeks off diet schedule, and benefits were maintained for 6 months after the diet was halted. This isn't much, and there are issues with deciding that ketosis itself was the beneficial factor in the autism trials - maybe if you are eating MCT oil and fresh cream for most of your calories, you are avoiding all sorts of other inflammatory stuff, but... a lot of systems in the body work in phases. And those high carb (though high coconut) Kitavans don't have dementia either... so if you ask me to balance what could be a risky endeavor (chronic never-ending ketosis - some of the kids in the epilepsy trials died of selenium deficiency, for example) versus a more flexible, and for those of us without epilepsy or possibly dementia, more "natural" path of eating when we have food and IFing a few times a week, I'm going to go with the IF route.

    That said, ketogenic diets have been refined over the years. Both Dr. Parker at Diebetic MEditerranean Diet Blog and Dr. Jaminet at PErfect Health Diet blog have nice and micronutrient-rich ketogenic diets to be used for weight loss, for example, especially in the case of metabolic syndrome or diabetes.

  7. Cavegirl - that's a great link. Thanks!

    Nigel - I saw your comment over at Nephropal about your mother. I'm glad she's doing better and that her GP is not too rigid to ignore your stacks of evidence.

    Jake- I'm certain you are much more of an autophagey expert than I am! I've read a few of the rat and C elegans papers, and of course many secondary sources by this point. It took me a while to build up as I had many years of every three hour eating behind me, plus some very negative Pavlovian associations to going without food from pregnancy and breastfeeding. But now I try to throw in a 24 hour IF once a week, and another 16 hours once or twice. Since I eat moderate carb otherwise (one fruit + a serving of starchy veg daily, or maybe just the starchy veg is typical) it is pretty easy for me to drop into ketosis with both these endeavors. I'm hopeful autophagy is going on!

  8. Jake, would you mind sharing a few details from the Autophagy Journal paper you quoted? Were these animal studies or human? And from the context of your comment it sounds like a 16 hr. fast is indeed sufficient to induce some level of autophagy. True?
    Like yourself I'm in my 60's and as I have a family history for Alzheimer's I'm pretty dedicated in the prevention department. Obviously, if autophagy is the real deal for moderating protein folding etc. and if autophagy can be relatively easily induced a whole new world of possibilities present themselves. Exciting, to say the least. Thanks.

    And thanks Emily for the always interesting (and funny frequently) blog.

  9. I think is the leading expert in autophagy and aging is Anna Maria Cuervo. She recently made an exciting discovery by finding the automatic autophagy receptor.

    This receptor detects damaged cell components and automatically forces autophagy to do a clean up to keep cells functioning efficiently. This can occur overnight as long as the insulin levels are low enough.

    However, as the cell ages the autophagy receptor loses its ability to detect damaged cell components, and no automatic cleanup occurs, The build up of damaged cell components put the cell in a diseased state including cancer.

    It is also possible that people can develop genetic defects in that autophagy receptor and that causes neurological diseases.

    The good news is that autophagy can be forced no matter how old the organism is by total fasting in a low insulin environment. Thus intermittent fasting will keep cells in a youthful condition.

    Cuervo believes that lack of autophagy is the main driving force for aging. I now believe she is correct.

    She is also a conventional wisdom nutrition believer so she thinks no one can do intermittent fasting. Thus she and others are desperately looking for a safe drug that will force autophagy.

    We who eat paleo and do IFing have already found our "autopsy drug" and it does not cost $50,000 a year.

  10. Greetings,
    Here is a link to papers exploring autophagy:

  11. Peter M:

    You are excited? I am jumping up and down excited about what I am reading in these autophagy papers.

    Most of the papers are I read are experiments on mice. Autophagy is a very ancient process used by all living things including plants to keep its cells healthy. Autophagy experiments on bacteria work on worms. Autophagy experiments on worms work on mice. So there is no reason not to believe that the experiments on mice will not work on humans.

    Fasts of 16 to 20 hours seem to be the sweet spot for getting insulin levels as low as possible. At those low insulin levels we assume that forced autophagy is taking place.

    Art De Vaney is proof that forced autophagy works in humans ( as I am). I think he invented the concept of intermittent fasting in the 90's. So he has been doing intermittent fasting for many years. I know Art as we both live in the same town in Utah. Although he is 73, he is very youthful both mentally and physically. So I follow his lead in diet and exercise.

    You might want to read his new book "The New Evolution Diet." I think he has got it nailed as far as achieving low insulin levels which are vital for us older people. I think his book is the old guy's paleo bible.

  12. Jake, thank you for the reply. If I'm not digressing too far from Emily's original post do you Jake, or you, Emily, hold the view that slightly more extended fasts supplemented with, say, coconut oil induce autophagy as effectively as a zero calorie fast? It's a critical distinction if one is approaching the fast from a 'preventing neurological disease' perspective. Paul at Perfect Health Diet seems to support that idea and honestly, I'm just trying to pin it all down for myself. Thanks again.

  13. Paul is wrong to suggest using coconut oil during a autophagy fast. The lauric acid in the coconut oil will stimulate an insulin response. That insulin will stop autophagy dead in its tracks.

    No, if you are doing a autophagy fast, you are better off using water and nothing else.

    However, I do use coconut oil during non-fasting periods.

  14. The only thing I can add (and again, this is all speculative in humans when you get to clinical applications, as far as I know) is that I've seen many reports of skin tags and warts and other signs of hyperinsulinemia disappearing with low protein or IFing, but not with straight-up low carbing. It occurs to me that might be an autophagy thing, but again I'm speculating. I think with IF you have to balance fasting with adding stress and increasing cortisol. Thus I think diminishing returns beyond 24 hours

  15. Dr Deans:

    I agree with what you are saying. If you did chronic fasting, the cells would not longer think it is a temporary starvation situation but that death is imminent. Autophagy would stop as it would be too destructive.

    Fasting has to be intermittent and random.

  16. Just wanted to add there are energetic benefits from ketosis for mitochondria apart from the autophagy bit - beta hyroxy butyrate seems to bypass a step in processing that is required by glucose

  17. re ketosis: just a thought, substantiated by a personal n=1 experience, is that ketosis (zero carb+fasting for a couple of days) is good way to lower your fat level 'set-point', after which you can eat your maintenance level of calories from usual sources without rebounding back

  18. Emily you really need to read Nick Lane's latest book on mitochondria and aging and disease. One of the best books every written. Chapters 15-19 would keep you spell bound. Its all about limiting leaky mitochondria. Name is call Power Sex and will love it and it will create many blogs. Dr. K.

  19. for a closer focus on mitophagy... FUN!


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