What caused all this?  Can the epidemic be reversed?  And what can you do if you suffer from asthma, allergies and autoimmune disease?

Many who follow this site are generally sympathetic to the “paleo” hypothesis: namely, that allergies, autoimmune disease , and other degenerative diseases are the spawn of neolithic agents — such as wheat and other grains, and legumes, introduced during the transition to an agrarian society  about 10,000 years ago.  These neolithic foodstuffs expose us to higher levels of carbohydrates and novel proteins and anti-nutrients — such as gluten, phytic acid and lectins — that our evolutionary history as primates did not adapt us (or at least many of us)  to tolerate.   There is a lot of evidence to support this idea — from archeology and comparative anthropology, to studies in genetics and immunology.

But is it true?

There is an alternative explanation that has now been put forward, based upon a revolution in immunology during the past decade.  Like the paleo hypothesis, this new theory is grounded in evolutionary biology, and it likewise sees our modern lifestyle as an evolutionary anomaly.  But this new perspective places the advent of the twin epidemics of allergy and autoimmunity — and more generally inflammatory disorders — not at the introduction of agriculture, but much more recently:  at the upswing and aftermath of the Industrial Revolution. And it identifies the causal agent not as the addition of neolithic foods, but rather the subtraction of a key protective factor that we’ve lived with since the beginning of human evolution, or even mammalian evolution.

The agent of our immunological misery is the disappearance of something we co-evolved with in a mutually beneficial relationships:  microbes and parasites that have lived inside our bodies for millennia.

This new hypothesis is brilliantly summarized in a recent book by Moises Velasquez-Manoff:  An Epidemic of Absence: A New Way of Understanding Allergies and Autoimmune Disease.  In 307 pages the author, a science writer, synthesizes a diverse range of research, interviews and adventures into a detective novel that ends with a quest to treat his own rare autoimmune disorder.  The book is both compelling and honest in probing both the promise and the limits of the arguments and evidence for this new perspective on practical immunology.

This new view leads to some unorthodox ideas about how to combat allergies and autoimmune diseases.  Some of the ideas being tested may seem wild to you.  But I’ll end with one very safe recommendation that makes good sense to me now, despite earlier doubts, and which I’ve already implemented with great gusto.

Too clean?  The message of this book may sound familiar to you:  It has the ring of the  ”hygiene hypothesis”: the thesis that our twin epidemics of allegy and autoimmunity arise from an environment that is in some sense “too clean”.  I discussed the hygiene hypothesis two years ago in my post “Allergies and hormesis“.  There, I summarized research indicating that the allergic response represents an over-reaction by an immune system that was not adequately “educated” by exposure to foreign environmental substances like bacteria, parasites, dander and proteins — particularly during early childhood.  As I wrote,

The adaptive immune cells (B and T) cells develop normal responses only if they are stimulated by exposure to foreign substances…Children get primed with IgG antibodies from their mother and IgA antibodies from breast milk which provide “passive” immunity for the first two years of life.  After that, children need to begin activating their own adaptive immunity – their own IgMs and IgGs….If this process of educating the adaptive immune system is not sufficiently activated in early childhood, the immune system of the adolescent or adult remains underdeveloped.  Then the response to foreign bodies relies more on the “emergency” system, using IgE antibodies instead of IgG, IgA, or IgM antibodies. It is these IgE antibodies that tend to overreact, causing allergies. Essentially, an “under-trained” adaptive immune system, such as that of someone raised in a sterile environment, is more prone to confuse harmless foreign bodies like pollen, dog hair, peanuts, eggs, or insect venom, for parasites. Their IgEs become sensitized towards these allergens, attach themselves to the mast cells on mucous membranes or beneath the skin.  Once the allergen reappears, a full-blown chemical attack, including histamine release, is initiated.

Stated this way, the hygiene hypothesis has a certain plausibility to it.  As a broad explanation, it makes sense.  But it doesn’t explain certain things:

• Children who grow up in cities have triple the rate of allergies as those who grow up on farms. Allergies are rising in urban environments where children are exposed to dust mites and dander even at an early age.  Why doesn’t that early exposure to allergens suffice to “prime” their adaptive immune systems ?
• Even if one grants the role of a cleaner environment, people respond in different ways.  Why do some people get specific allergies, and others develop certain autoimmune diseases?  What explains the differential response that leads to asthma, celiac disease, or multiple sclerosis?
• The rise of obesity, cardiovascular disease and metabolic syndrome parallels the rise of immune disorders.  Can these be linked to a common cause?

Co-evolution. Velasquez-Manoff rescues, refines and elevates the hygiene hypothesis, putting it on firmer ground by framing it in the context of a key insight about our evolution.  Our long evolutionary history inextricably entwines us with a diverse set of microscopic companions who have been along for a long ride.  These companions are a collection of microbes, parasites and viruses who have been fellow travelers from our earliest origins.  These infection agents have at times caused illness and death, and our immune systems defend us against them with varying effectiveness.

But here’s the new insight:  they’ve been with us so long, that we now depend upon them.  And removing them from the scene has harmed us. That sounds strange.  How can removing an “enemy” be a bad thing?  It could be, if the enemy is a recent invader.  But what if you have lived with the “enemy” for a very long time?

One of the protagonists of “An Epidemic of Absence” is University College London immunologist Graham Rook.  In the book, Rook is described as the “godfather” of the hygiene hypothesis, recasting it in a new, more accurate and more interesting light:

In the late 1990s, he insisted that the then-dominant model of immune function–two immune response types, the pursuit of microbes and the repulsion of parasites, cross-regulating each other–was incorrect. A third peacekeeping arm, which prevented both autoimmiune and allergic disorders from arising, was key–a view that has since achieved orthodoxy. (Epidemic, p. 110).

This third “peacekeeping arm” — a kind of police to oversee the police — is made up of regulatory T cells, called “T-regs” for short.  The first line of B and T cell immune cells work by activating an inflammatory response that goes after invading bodies.  While effective, this inflammatory can get out of hand and inflect collateral or “friendly” fire.  T-regs provide an anti-inflammatory response that keeps the first responders in check.

Finding the emphasis on “hygiene” misleading, Rook rechristened the hygiene hypothesis the “old friends” hypothesis.  Major infections don’t help the immune system, he argues.  If anything, acute inflammation makes things worse. A very specific group of organisms meets the “old friends” criteria–organisms that have accompanied us since the Paleolithic.  That includes worms, cowshed-type microbes, lactobacilli, and our own fecal bacteria. It doesn’t include, however, measles and your everyday cold virus.  Evolutionarily speaking, these are latecomers. They arrived after the domesication of animals, and after humans had aggregated in crowds sufficient to sustain them. (Epidemic, p. 110-111).

The list of “old friend” organisms–”house guests” with whom we’ve coevolved long enough to develop a mutually beneficial relationship–includes parasites like hookworms, parasitic bacteria like mycobacteria (including M. tuberculosis), Helicobacter pylori, and saprophytes — nonparasitic “pseudocommensals” that are ever-present in  dirt and (unfiltered) water.

Outsourcing immune regulation. But how did these foreign organism come to be welcome residents, rather than invaders to be repelled in defense of the homeland?  Graham Rook responds to this question with two pithy phrases:

Contact with another organism–saprophytes say–develops your immune regulatory circuits. Over evolutionary time, the ability to regulate immune function yourself dulls or disappears. Losing this capacity incurs no immediate cost, however. Saprophytes are ubiquitous, and contact with them is unavoidable.  Nonetheless, you’ve outsourced your immunoregulation to microbes. Now you’re dependent on them. (Epidemic, p. 113)

The Industrial Revolution.  Until the last few centuries–when most humans lived as hunters,  as farmers, or in small settlements–our immunological reliance on cohabiting microbes and parasites involved  redundancy. We weren’t dependent on any single organism.  But then two dislocations took place.  First, industrialization brought with it an intense urbanization and crowding that resulted in the spread of infectious disease.  We are all familiar with the epidemics of tuberculosis, pneumonia, influenza, polio and other diseases that felled millions, often in early childhood.

Hopes and treatments.  Understanding causality doesn’t automatically lead us to effective treatments.  It may well be true that removing parasites and diverse intestinal microbes from our midst has provoked the current epidemic in autoimmune disease, allergy and other manifestations of an under-regulated immune system.

But that doesn’t mean that re-introducing these “old friends” will always reverse these conditions, or that it is yet possible to use deliberate infection as a therapy.  All these infective agents can be double-edge swords. Moises-Velasquez notes the importance of timing in the nature and effectiveness of how bacteria, viruses and parasites “educate” and moderate the inflammatory tendencies of our immune systems.  Timing is key!  Early exposure to Eppstein-Barr virus, Helicobacter pylori, and M. tuberculosis can be protective, whereas too late exposure can cause autoimmune disease, cancer, and respiratory disease.

There is an emerging field of “helminthic therapy” much of it underground.  People are deliberately infecting themselves with hookworms and other parasites,  encouraged by the developing science, but equally out of desparation.  The successes are many and are impressively documented in his book. But Velasquez-Manoff honestly reports on those who fail to respond or suffer setbacks — including his own experiences using the worm Necator americanus to largely banish his hayfever, yet produce only minor improvement in his alopecia universalis, a rare autommune disease that attacks body hair.

What would I do?  I’m fortunate not to suffer from asthma, allergies or autoimmune disease.  Yet these conditions are prevalent among friends and those close to me — my wife has multiple sclerosis.  So it’s not just an academic question. The science is exciting, and I intend to follow it.  But it’s still early days. I’m not so adventurous yet as to advocate or try helminthic therapy, fecal transplants — and certainly not deliberate infection by viral agents.  I’m not that much of an early adopter.

But there is one practical insight I take from Graham Rook’s “old friends” hypothesis:  the idea that in our long evolution, we outsourced our immune regulation not to any single organism, but to a diverse network of microbes, parasites, and viruses that live within us.  Which means that there are probably many different organisms and combinations of organisms that we turn to in achieve immune moderation.

For that reason, I think the safest and most robust set of microbial helpers may be those in our  gut — our microbiome.  We frequently hear that the bacteria in our intestines outnumber all the other cells in our body by a factor of ten.  More importantly, the genetic diversity and metabolic pathways provided by gut bacteria outstrips that of our human cells.  We intimately depend upon them to derive nourishment from our food, and we have outsourced many other functions to them. So why not take this seriously and pay more attention to the microflora that live in our intestines?

Gut health.  It is increasingly apparent that the composition of bacteria in out gut has major effects on our health.  Shifting the gut population away from pro-inflammatory species like bacteriodetes and towards anti-inflammatory species like bifidobacteria and lactobacilli has systemic benefits that appear to tip that balance away from metabolic and immune disorders and towards health. These beneficial microflora have been shown not only to help police the immune system, but to keep the intestinal barrier intact and reduce the risk of diabetes. In addition, these good bacteria convert this indigestible fiber into short chain fatty acids like butyrate that not only provide a sustained sourced of energy, but support the health of the intestinal lumen.  Ironically, you could say that a high fiber vegetarian diet is a “high fat” diet!

While “transplants” may be a dramatic way to colonize the gut with the good bugs, I’m most impressed by a simpler route:

We should be sure to include ample amounts of prebiotic fiber in our diet

A year ago, I never thought I would advocate a high fiber diet.  I thought of fiber as inert “roughage” , or a means of  reducing the glycemic index of fruits and other carbohydrate rich foods, by slowing the release of sugars during digestion.   But now I see fiber through entirely different eyes:  as “food” required by the microbes we co-evolved with and rely upon intensely for our health.  The most important type of fiber is soluble fiber, particularly fructooligosaccharides and other non-starch polysaccharides that we can’t digest without the aid of bifidobacteria, lactobacilli and other beneficial bacteria.  To ensure a robust colonization of our gut by these microbes, we don’t need to “eat” them as probiotics and yogurts or transplant them through the rear end.  The most natural way to colonize your gut is to feed them by eating a high fiber diet, and to minimize the sugars that lead to intestinal “blooms” of deleterious bacteria like E. coli and C. difficult — which you might think of as “intestinal weeds”

In recent months, I’ve significantly increased the volume of green, leafy cruciferous vegetables in my diet — such as kale, broccoli, brussel sprouts;  colored and bitter fruiting bodies like red and green peppers, herbs and spices like curcumin.  The original impetus was a natural way to add polyphenolic phytonutrients that activate the endogenous antioxidant enzyme systems — as I discussed in my post, The case against antioxidants.  But my newer reason for doing this is to keep the “old friends” in my gut happy and working on my behalf.  Other than basing this decision on the science, I can’t yet point to personal benefits of this regimen, other than limitless energy, no cravings, and a virtual absence of post-workout soreness or pain.  Of course, fiber can be introduced from a great variety of vegetable sources beyond the cruciferous ones.  Avocados, artichokes strawberries, mushrooms, sweet potatoes…the list goes on.

So we come back to a “paleo” diet,  replete with healthful meats, fish, and nuts —  and abundant with green and colored fibrous plants.  But the justification for such a diet is not the traditional paleo line of avoiding ”novel” toxins and antinutrients in grains, starches, and processed foods, so much as it is one of fortifying our defenses by feeding the peacekeeping armies of microflora that live inside us, balance our immune systems, and provide us with a sustained source of short-chain “fat” energy.  We should think of our gut microflora not as invaders or visitors, but literally as integral parts of our body — what Velasquez-Manoff calls our “superorganism”.

During our evolution, we outsourced these important protective functions to the gut microbes — so we need to keep them happy by feeding them well.  Maybe it took the epidemics of autoimmune disease to teach us to appreciate the essential role that microflora play in our health.

Some readers got the idea that I believe vitamin D is not beneficial, and that I discount the evidence from studies that show the benefits.  I want to dispel that notion.  I do acknowledge the key role that vitamin D and the vitamin D receptor (VDR) play in bone mineralization and regulation of  innate and adaptive immunity, and among other things.  I further acknowledge that many (but certainly not all) studies support an association between higher vitamin D3 levels and reduced incidence of diseases such as cancer.

As I wrote:

Nobody doubts the important role of vitamin D in the body. But are higher levels of a hormone like vitamin D–whether or not provided as a supplement– always a good thing?

My doubts are focused on several points:

• Under-appreciation of the fact that vitamin D is a hormone with diverse and dose-dependent systemic effects, still not fully understood
• Misleading  claims that vitamin D supplementation is “equivalent”  to vitamin D from sun exposure. While the two forms are chemically identical, levels of vitamin D3 synthesized from sun exposure are self-limiting due to feedback regulation.  What happens when we chronically exceed natural limits?
• Inadequate attention to the possible effects of chronic vitamin D supplementation on homeostatic down-regulation of the VDR receptor. See this discussion bv Dr. David Agus of USC medical school.
• Inadequate study of the possible long term adverse effects of chronic vitamin D supplementation. Few studies look beyond 4 years. Hormone replacement therapy was in favor for 50 years before the risks came to light . Things don’t necessarily look any more promising when synthetic hormones are replaced bioidentical hormones.

My article created a dilemma for several commenters. These people acknowledged the risks, but nevertheless cited  benefits they personally experienced  from supplementing with vitamin D–ranging from fewer colds and flu, to relief of autoimmune symptoms, and even lessening of depression.

For these people, a key question remains:

Is there a way to get the benefits of vitamin D supplementation, while avoiding the dependency and risks of taking vitamin D capsules daily for the rest of your life?  While I don’t have a definitive proven answer to that question, recent research leads me to speculate here that there is a promising approach that is within everyone’s reach.

It lies within a powerful natural biological process called autophagy.

What is autophagy?   This term  derives from the Greek roots for “self eating”.  It refers to a process that normal cells in every organism can use to derive energy by breaking down and recycling unneeded or “damaged” components.  Autophagy typically kicks in when a cell is  temporarily deprived of externally supplied nutrients, or subjected to other stresses such as low oxygen, infection and chemical exposure.  In the most common type of autophagy–known as macroautophagy–the cell constructs a special membrane enclosure, called an autophagosome, that floats around inside the cell.  The autophagosome is a kind of miniature recycling factory that detects, engulfs and digests damaged proteins and larger organelle structures.  After trapping the cellular components, the autophagosome fuses with a packet of degradative enzymes, known as a lysosome.  It then degrades these large molecules down to their component amino acids, sugars and fatty acids, which can be used as fuels and building blocks for repair and growth.  This recycling of damaged parts ensures an uninterrupted supply of energy and structural components need by the cell.

But the benefits of autophagy go far beyond fueling the cell, and ridding the cell of useless “junk”. Autophagy’s cellular housekeeping function actively counteracts many of the degenerative processes of aging!

Damage to cell structures and proteins is cumulative, and if allowed to proceed without correction, it can lead to malfunctioning of cellular processes and the genesis of illness. For example, a diet high in reactive sugars such as sucrose and fructose can glycate proteins, creating cross-linked structures known as advanced glycation end-products (AGEs), Similarly, oxidative stress can damage lipid bilayer membranes. The accumulation of these abnormal molecules has been implicated in the genesis of degenerative diseases such as diabetes, Alzheimers, cardiovascular disease and stroke.  Autophagosomes have also been shown to engulf and remove intracellular pathogens, such as the tuberculosis bacterium. Most intriguing, while autophagy regenerates the viability of normal cells, it has been show trigger the self-destruction (apoptosis) of some cancer cells and other abnormal cells.  In short, regular and recurrent autophagy is a key defense against a range of degenerative diseases.

The vitamin D connection.  What does autophagy have to do with vitamin D, you ask?  In mammals, the vitamin D receptor (VDR) sits at the beginning of a important cascade of biochemical pathways. Vitamin D3 or 25-D, from supplements or cutaneous synthesis, is converted to the active 1,25-D form in the kidneys in response to pituitary hormone (PTH).  Renal 1,25-D plays a key role in the regulation of bone mineralization and waste excretion. But the VDR is also distributed to widely in cells throughout the body.  After the kidney has converted vitamin D3 (25-D) to the active form of vitamin D (1,25-D) it is transported through the circulation to extra=renal sites by a protein known as vitamin D binding protein (VDBP).  Within the cell, the active vitamin D  interacts with the VDR to provide local control of a range of metabolic functions, including cellular immunity, anti-inflammatory, anti-infective, and anticancer responses.

And recent research indicates that one of the key functions of the VDR is to regulate autophagy!

Studies by several research groups have elucidated this signaling pathways that connect the VDR and calcium metabolism to autophagy. According to Shaoping Wu and Jun Sun at the University of Rochester Department of Medicine,

The signaling pathways regulated by vitamin D₃ include Bcl-2, beclin-1, mammalian target of rapamycin (mTOR), the class III phosphatidylinositol 3-kinase complex (PI3KC3), cathelicidin, calcium metabolism, and cyclin-dependent kinase (Table 1). These pathways are critical in host defense and inflammatory responses. Hence, vitamin D₃ and autophagy are associated with innate immunity…Vitamin D₃ is a major regulator of calcium metabolism. Increased circulating vitamin D₃ activates VDR, leading to increased intestinal calcium absorption. In excitable cells such as neurons, calcium is released from the sarcoplasmic or endoplasmic reticulum (ER) to activate calcium-dependent kinases and phosphatases, thereby regulating numerous cellular processes, including autophagy. ER calcium induces autophagy when stimulated by vitamin D₃. This process is inhibited by mTOR, a negative regulator of macroautophagy, and induces massive accumulation of autophagosomes in a beclin-1- and ATG7-dependent manner since they are not fused with lysosomes. Vitamin D₃ can down-regulate the expression of mTOR protein, thus inducing autophagy by inhibiting the mTORC1 complex.

A review by Høyer-Hansen et al., of the Institute of Cancer Biology at the Danish Cancer Society, elucidates the mechanisms by which vitamin D (“VD” here) induced autophagy selectively target cancer cells:

VD analogs are potent inducers of autophagy in different cell types, and autophagy is crucial for their cytotoxic activity towards cancer cells….[T]he signaling pathways connecting VD compounds to autophagy induction are similar in breast cancer cells and monocytes [7,12]. Autophagy induction in both cell types relies on an increase in [Ca2+]cyt, which could result from VDR-mediated changes in the expression levels of calcium-regulating proteins and the subsequent endoplasmic reticulum stress.

…Autophagy usually exerts a cytoprotective function in stressed cells; however, in EB1089-treated breast cancer cells, the enhancement of the autophagic response by ectopic expression of Becn1 increases cell death… Importantly, 1a,25-(OH)2D3-treated primary monocytes do not show any signs of cell death even though their autophagy response is similar to that observed in cancer cells. Thus, it is tempting to speculate that 1a,25- (OH)2D3-induced autophagic cell death could be specific for cancer cells; if true, this would represent a new cancer-specific treatment.

The Danish group has also shown that vitamin D acts to contain and eliminate the tuberculosis bacterium by inducing autophagy, perhaps providing an explanation for the historical use of cod liver oil and vitamin D as early therapies against TB  before the advent of antibiotics:

In tuberculosis, M. tuberculosis resides in phagosomes and evades host antimicrobial mechanisms by blocking phagosome maturation and fusion with the lysosome. Ultimately, the host must overcome this evasion strategy to destroy the pathogen. Accumulating evidence suggests that this occurs via the autophagic degradation of bacteria-containing phagosomes and the subsequent killing of the bacteria in autolysosomes. Interestingly, a recent paper links the 1a,25-(OH)2D3- and autophagy-controlled antimycobacterial defense-pathways.

They conclude:

Recent data link autophagy to two of the beneficial effects of VD: the induction of cancer cell death and the clearance of M. tuberculosis. This opens the possibility that autophagy could be a general mediator of the health-promoting effects of 1a,25-(OH)2D3. Accordingly, there is a striking overlap among the diseases promoted by VD deficiency and defective autophagy. The new data linking the two health-promoting pathways open an interesting research field that could lead to new options for the treatment and prevention of many common diseases.

All very interesting. But if the vitamin D receptor is an activator of cellular autophagy, with its many apparent health benefits is there a way to activate the process without taking vitamin D capsules or spending all day in the sun?

How to activate autophagy without vitamin D.   While vitamin D is one potent way to turn on the autophagy switch, it’s by no means the only way. Autophagy is a phenomenon that occurs throughout the animal kingdom, not just vitamin D utilizing mammals like ourselves. For example, Morselli et al. have shown that autophagy is a requirement for the demonstrated life-extending benefits of caloric restriction in nematodes, mice, flies and worms.

In fact there are several ways you can naturally activate autophagy in your body.  It turns out that all of them involve one form of hormesis or another:

• Calorie restriction and intermittent fasting.  In my post on Calorie restriction and hormesis,  I summarized some of the research on calorie restriction in humans, primates and other animals. including the role played by autophagy and other mechanisms.  This is also described in my talk on Intermittent Fasting for Health and Longevity.
• Brief, strenuous exercise.  A 2012 paper in Nature by Levine et al. in mice found that “Exercise is even faster than starvation” at inducing autophagy… “If you just exercise the mice for 30 minutes on a treadmill, autophagosomes start to form. Thirty minutes of running induces autophagy 40 to 50 percent.”
• Hormetic stress in general.   A wide range of short term, intense but sublethal stressors have been shown to activate autophagy via a common pathway.  Criollo et al.  showed that multiple stressors, including nutrient starvation and numerous chemicals, trigger the activation of the IKK (IκB kinase) complex, inducing the classical autophagy pathway involving p53 depletion, mTOR inhibition, AMPK and JNK1 activation, and release of the pro-autophagic protein Beclin-1.  How many of the other hormetic stressors we’ve discussed in this blog– such as cold showers–might effectively activate autophagy?

Why I prefer natural stressors.  So perhaps you might be persuaded you to at least consider trying intermittent fasting and exercise (better yet: fasted workouts) to activate your autophagy. If you are one of those who finds that vitamin D helps reduce colds or asthma symptoms — try skipping meals and snacks, and cut back on carbohydrates and excess protein.  I eat one or two small meals a day, mostly low carb or Paleo, and I can’t remember the last time I had a flu or cold.

But taking vitamin D supplements is so much more convenient, right?  I mean — why go to all the effort to subject yourself to uncomfortable hormetic practices when you can just pop a tiny, inexpensive gel capsule once day?  Or even if you go in for exercise and intermittent fasting, why not hedge your bets and throw in vitamin D supplementation too, just to strengthen the brew?

Ultimately a decision like this is a personal one.  You can read all the studies and science that’s out there, but each of us has a different way of balancing considerations of risks and effort, science and intuition.  I can’t make that decision for you.  But I’ll leave you with one thought:

The human species has existed on earth for about six millions years, mammals for 160 million years. Basic cellular defense and repair mechanisms, including autophagy, have played an essential role in protecting us against degenerative diseases during most of that history.  Real world stressors act broadly and in a varied manner. And we have evolved to experience these stressors in their full variety. As Art DeVany likes to point out, real world stressors have  ”fractal” pattern that keeps our metabolisms guessing. To the extent that vitamin D is protective against these diseases, it is likely because vitamin D activates the autophagy signaling pathways. But as David Agus notes in the video I linked above, vitamin D hits a single node in the signaling pathway. Supplementation protocols provide the same fixed amount of vitamin D, day in and day out.

Our ancestors did not have access to a highly purified, concentrated vitamin D pills to activate their autophagy at a fixed dosage every day.  They did it the old-fashioned way:  they “earned” their autophagy with natural and varied stressors like intense physical activity and more sporadic access to foods (and foods with lower insulin and mTOR activation potential).  And they got their vitamin D from the sun and certain fatty foods — again in a varied pattern.

This old-fashioned way of activating autophagy is a experiment that has been running for millions of years. Chronic, life-long supplementation with high doses of vitamin D is a relatively recent  innovation. Do you want to be so dependent on a single compound you take every day?  What happens if you are away from civilization for a few days without your vitamins?

The choice is yours.

In this post, Nate focuses on an interesting case where “controlled stress” is particularly useful: the treatment of phobias by exposure therapy.  

Exposure Therapy

Exposure therapy has interested me since my days in medical school. It is a very effective, but often underused therapy for phobias, Obsessive-Compulsive Disorder (OCD), and anxiety.  In writing this post, I have relied on David Tolin’s excellent book, “Face Your Fears“.  I highly recommend it.

When fear becomes a problem. Fear is a natural emotion, necessary for our survival. A good analogy for how fear works is a car alarm system.  A well-functioning car alarm system protects our car by alerting us when someone is attempting to break in.  A car alarm which constantly goes off, however, is more harmful than helpful. In the same way, some people have a “broken” fear system, in which fear becomes hyperactive, turning into anxiety. Common anxiety disorders include panic disorder, agoraphobia, phobias, social phobia, OCD, generalized anxiety, post-traumatic stress disorder, and separation anxiety disorder.  All of these are categorized as specific disorders, they have many features in common, and all respond to exposure therapy. While exposure therapy is primarily used for dealing with pathologic fears, it can also help us deal with routine fears which aren’t severe enough to be pathologic. For instance, most people have some fear of public speaking–but not to the degree that it is pathologic.  The same principles apply in overcoming non-pathologic fears. Towards the end of this post, I’ll give some examples on how I’ve used exposure therapy to deal with my own fears.

Fear is necessarily unpleasant because its “purpose” is to help us stay safe by avoiding dangerous situations.  However, when it becomes overactive, our entire life can be unpleasant. Exposure therapy deliberately ‘exposes’ us to fear in order to help us learn how to bring it under control and experience it in a normal way.  I need to emphasize that one of the primary objectives in exposure therapy is to feel the fear.  That’s right–our goal is to feel fear, and then to learn to deal with that fear.

How exposure therapy works. The basic concept of exposure therapy is quite simple: you overcome fears and phobias by directly exposing yourself to them.  But that doesn’t mean it is easy to carry out in practice.  An experienced therapist can be a big help.

Let me give an example of exposure therapy to treat a fear of snakes.  If you fear snakes, you should first make a list of possible exposure experiences, and then rank these from hardest to easiest, with 100 being intolerably high fear, and 0 representing no fear at all:

After making this list, conduct the exposure sessions.  Start with an item relatively low on the list, and continue the exposure session until the fear level drops at least in half.  In this example, approaching a snake cage might be too difficult, so you could start by looking at pictures of snakes.  Continue looking at these pictures until the fear level drops from 40 to 20. Then proceed to the next higher item on the list. Watch movies about snakes–maybe Nature specials–until the fear level drops in half. Continue to move upward in the list of exposure experiences, until the fear is completely mastered.

While a therapist can be helpful, the exposure is what counts. In his book, Tolin documents that many people do quite well with a self-help book. He normally gives a copy of his book to clients, and most do well with just the book. Those who don’t, he sees in consultation.

Exposure therapy can be time-consuming and unpleasant, so why do it? Is it really effective? Phobias and OCD can be very debilitating. But once the fear is overcome, quality of life greatly improves. In controlled trials, the initial effect of exposure therapy is approximately equal to that of medication. However, over time, the effect of medication wanes, while the effect of exposure therapy actually becomes stronger. In addition, many of the medications often used to treat anxiety are addicting, and have harmful side effects. Of these medications, the benzodiazepines (Xanax, Valium) are particularly addicting and harmful–over time they often increase the anxiety.

There are four main theories on how exposure therapy is thought to work:

• Habituation.  Just as you acclimate to cold water after the initial shock, when you face something fearful, you get used to it, and you stop responding to it in the same way.
• Extinction. According to classical Pavlovian conditioning theory, fears dissipate or extinguish when they are not reinforced. For instance, if you have fear of dogs, perhaps at some point in your life you had a scary experience with a dog barking or biting. From that point forward, you associate the sight of dogs with those fearful experiences. Yet, by exposing yourself over time to dogs without new adverse consequences, you retrain your brain to understand that “dog does not equal bite”, extinguishing the original association.
• Emotional processing theory. Particularly in the case of social phobias, the brain attaches exaggerated emotional meanings to ordinary events. You might fear that stuttering would result in catastrophic embarrassment. A key part of exposure therapy is learning that while you might stutter, the consequences are not catastrophic.
• Self efficacy theory.  This theory was pioneered by Bandura and applied to treatment of phobias by Williams. People who live with fear and avoidance often live in a world of “I can’ts”.  They consciously or subconsciously tell themselves “I can’t do this”, “I can’t donate blood”, “I can’t speak publicly”, “I can’t ask that cute girl out”,  etc.  When you face a fear without retreating, you begin to feel stronger.  The “I cant’s” in your brain begin to be replaced by “I can”.

While each of theories has some validity and helps explain the success of exposure therapy, I think that the self-efficacy theory is the most powerful of the four.  There is nothing as empowering as the feeling of self-confidence that  comes from doing hard things successfully. Taking a medication for anxiety will not give you a feeling of self efficacy.

Success factors.  A number of important key principles underlie successful exposure therapy:

1. Exposures should be voluntary.  If your friend has a phobia about snakes, throwing him into a snake pit against his will is not likely to cure his phobia–in fact it will probably be so traumatizing that the phobia will get worse.  In order to be curative, the exposures should be voluntary.  Todd has a nice post, “Voluntary stress”, which expands further on this point.
2. Gradualism generally works best, but not always.  Some exposure therapists advocate  graded exposure while others suggest “flooding”, or facing the full-blown fear head-on. While most people prefer graded exposure, flooding has the advantage of working more quickly and effectively.  I have an example from my life in which flooding was the best option, which I’ll discuss below.
3. Expose yourself to the real object of fear. If your fear is public speaking, you should give lots of talks. The most effective exposure is the actual fear.  For instance if your fear is dogs, you should pet actual dogs. That is called “in vivo” exposure. However, sometimes you can’t easily expose yourself to certain real life fears.  For instance if your fear is flying, it may be too expensive to take multiple flights.  In that case you can use “imaginal exposure”, where you imagine in great detail taking a flight.  You might make an audio tape describing taking a flight and listen to it.  You might watch movies about plane flights.
4. Allow yourself to experience the fear. How long should an exposure session last?  Exposure is meant to be a learning process. If you face a fear, and retreat quickly, what have you learned? That retreating makes you feel better. But a premature retreat can make the fear worse, by reinforcing it. Psychologists call this process sensitization. A good rule of thumb is to continue the exposure until your level of fear diminishes by one half.  It’s even better if you can hold on until the fear vanishes entirely. That way, you are learning that fear will eventually decrease, even if you don’t withdraw. For instance if your fear is snakes, you might decide to do an exposure by looking at pictures of snakes, and continue doing it until the fear goes away on its own.
5. Vary your exposures.  If you have fear of social interactions, try to interact with people in as many different ways that you can think of.  Talk to strangers on the bus, to your professor, people at church, your mother-in-law, the cashier at the store, etc.
6. Repeat the exposure many times.  If you have a fear of public speaking, giving one short talk will not be enough. You need to give several, possibly many talks.  Every time you repeat the exposure you reinforce the “I can” circuits in your brain.

Finally, have a plan.  If you can write out a plan of exposures, listing when and where you will do them, you will be more successful.

Safety Behaviors.  In overcoming anxiety and phobias, avoidance is the enemy. When you do exposure exercises, you need to counteract the natural tendency to avoid fearful situations by resorting to what we call “safety behaviors”. For instance, if your fear is dogs, and you can’t avoid them completely, your might be inclined to carry pepper spray when you walk past the dogs, because it makes you feel safer, and enables you to walk past the dogs. But this safety behavior is counterproductive because it interferes with fully experiencing your fear.

People with OCD are very familiar with safety behaviors.  For instance, someone with OCD and anxiety about hygiene might have the compulsion to wash his hands frequently. The hand washing temporarily relieves the anxiety–but as with all forms of avoidance, over the long run it reinforces the anxiety and behavior.  Another example of OCD safety behavior is ritualistic religious behavior.  For instance, repetitive thoughts of sinful behavior may intrude into the person’s mind.  Temporary relief is obtained by saying a ritualistic prayer or repentance–but the compulsion, a safety behavior, reinforces the anxiety. For someone with social anxiety. a safety behavior may be going to a party with a friend, or socializing exclusively with people who they know.  But accompaniment by the friend prevents the person with social anxiety from interacting with strangers.

All of us have some anxiety, and some safety behaviors.  That’s fine as long as the anxiety and safety behaviors don’t intrude on our lives. But, as Tolin observes, a safety behavior can become a “crutch” that tends to undermine the effectiveness of exposure therapy.  When you use this crutch repetitively, you reinforce the anxiety and build weakness. In this respect, exposure therapy goes against the idea of resorting to relaxation techniques or distraction to reduce anxiety.  Because  exposure therapy works by confronting fears, these techniques are counterproductive in the quest to overcome the anxiety.

A better alternative is acceptance of fear. Tolin gives the analogy of Chinese handcuffs: the more you struggle against them, the tighter they hold you.  When you directly face or push into the fear, it very often diminishes.

The main point here is: Don’t relax.  Don’t distract.  Don’t try to feel better.  Don’t use crutches.  Instead, push into the fear.

Make a list of your safety behaviors, and eliminate them.  While Tolin recommends graded exposure, he recommends eliminating the safety behaviors completely from the beginning.

You need to feel the fear.

Specific applications. If you have a particular anxiety disorder, I’d highly recommend that you buy Tolin’s book, which goes into much greater detail than I can in this post. But to better illustrate how exposure therapy works, I’ll briefly discuss a few specific examples:

Obsessive compulsive disorder (OCD).  This anxiety disorder has two parts. Obsessions are recurrent and persistent thoughts that feel intrusive and inappropriate, and they cause the person anxiety and distress.  Compulsions are repetitive behaviors the person feels they must perform in response to the obsessive thoughts, often according to specific rules.  For instance, a person might have anxiety about hygiene (the obsession), coupled with excessive hand washing (the compulsion).  A religious person might have intrusive thoughts of a blasphemous or sexual, sinful nature-feelings of unworthiness (the obsession), coupled with a ritualistic  prayer, or the need to think “good thoughts” in order to neutralize the bad ones.

Note that the compulsions are a form of “safety behavior”.  While they cause a temporary relief from the anxiety of the obsession, over the long term, they perpetuate it.  Everyone has some intrusive and inappropriate, unwanted thoughts. There is evidence that people with OCD overreact to these thoughts,  and think their thoughts have more meaning more than they actually  do.  Those with OCD,feel compelled to control their thoughts.

Here I’ll give an example of how exposure therapy works for OCD with cleanliness as the obsession:  In the case of OCD, it is often helpful for the exposure therapy to go “beyond normal”.  Tolin recommends that a person with a washing compulsion stop washing altogether for three entire days.  Another suggestion is to touch as many doorknobs as possible–with no washing.  Both of these behaviors are objectively safe; people who don’t wash at all during a weeklong campout typically do not suffer any negative health consequences.  Likewise,  people touch doorknobs all the time without washing, to no ill effect.

The important point is to expose yourself to the obsession, without resorting to the safety behavior–the compulsion. With time, the obsession will extinguish.

Social anxiety.  Most people, while not having a pathologic anxiety disorder, probably have some degree of social anxiety.  While I don’t think I have a social anxiety disorder, I can recall a number of instances of mild social anxiety:

• Many times I’ve gone to a party and socialized only with people who I already knew.
• When I used to play the piano, I would often  practice a piece to the point of perfection alone, only to have performance anxiety on performing before an audience-and completely mess up the piece.
• While I frequently give public talks, I often become anxious before or while speaking.
• Back in my younger, dating days, I recall becoming nervous about calling girls for dates. At times, I definitely engaged in some avoidance and “safety behavior”.

Some degree of social anxiety, coupled with avoidance and safety behavior, is so common that it is almost normal.

To overcome social anxiety,  expose yourself to the uncomfortable, fearful situation. Don’t fight the fear, embrace it (remember the example of Chinese handcuffs).  If possible, continue the exposure until the fear drops by half. With social anxiety in particular, you may find that once the fear begins to drop, you actually enjoy the social interaction. You may make new friends or find that you enjoy your piano performance.

I have applied exposure therapy to my own discomfort with public speaking. I’ve tried to seek out and embrace the opportunities I have for public speaking. I’ve also tried eliminating safety behaviors–for instance speaking without a written copy of my notes.  I’ve also tried to have several different options for the “flow” of my talk, tried to get a feel for the audience, and taken my talk on different route depending on the feel.

Blood donation. This was actually the first phobia of mine that I can recall! As a child, while weeding a rosebush I cut my hand on a thorn–deeply.  I ran into the house.  As my mother was bandaging the cut.  I looked at it.  My hand seemed to be bleeding profusely.  In my young mind, I thought I was bleeding to death–and I passed out.  Later, while in college, a friend managed to sign me up for a blood donation. During class on the morning of the donation, the teacher just happened to talk about blood donations. As he talked, I began to feel light-headed.  I remember thinking “I might pass out”, and fighting that feeling.  Then I remember waking up on the floor of the classroom with my classmates gathered around–very embarrassing.

I first tried my own naïve form of exposure therapy for blood donations on several occasions–psyching myself up to donate blood, trying to relax and block the feelings of anxiety before  donating blood.  Once more I passed out.  Another time I didn’t actually pass out, but came so close to passing out that they had to stop the donation. Finally, I simply practiced avoidance: “I just don’t donate blood because I can’t”.

A blood donation phobia is a very minor one.  It is easy to live life without donating blood.  However, it always kind of bothered me.  After reading Tolin’s book, I decided to try to overcome it.  It never bothered me to merely think about blood donation. It was the actual act donating blood that made me anxious.

As soon as the blood drive came to our community, I signed up.  I eliminated all safety behaviors.  In the waiting room I read blood donation literature. When anxiety came, I didn’t try to calm myself, but rather embraced the anxiety: “This is why I am here–to feel this”.  I deliberately watched as they inserted the needle into my vein. I talked with other donors.

And what happened?  It was kind of anticlimactic.  The anxiety never came on very strong, and went away rapidly when it did.  I just sat in the chair, gave blood, and walked out.  Actually, no big deal.

While exposure therapy is a great way to deal with phobias and anxiety, it has applications for growth far beyond just overcoming negative experiences.  It is a way to begin experiencing real growth and to create positive experiences. Exposure therapy is a good example of hormesis–the application of stress to overcome weakness.

If you directly confront your fears, you can overcome them, rather than being limited by them.

Supplementation with vitamin D capsules is advocated even by “primal” advocate  Mark Sisson, normally one to take inspiration from our paleolithic ancestors, shunning medication and embracing a lifestyle of eating whole foods and engaging in moderately stressful, playful exercise:

We can’t all bask in the midday sun.. For those of us unable to run shirtless and shoeless through a sun kissed meadow…our option is oral intake… food will help, but it won’t suffice. You need something stronger. ..take a good D3 supplement if you can’t get real sunlight. As long as you don’t go overboard on the dosage, you’re good to go. If it’s not in an oil-based capsule, just take it with a bit of fatty food (not a stretch for an Primal eater). It travels the same pathway and results in the same benefits. It’s always easier to just let nature take its course, but it’s not always realistic. A good general rule is 4000 IU per day.

Therefore, we should supplement with vitamin D.  Right?

Not so fast.  A closer examination shows that low vitamin D levels may be a consequence, not a cause, of poor health.  And that supplementation with Vitamin D may actually be counterproductive.  Let me explain.

Homeostatic regulation.  First, I’d like to return briefly to a previous post I wrote.  In The case against antioxidants, I presented evidence that supplementation with antioxidants is not only unhelpful, but may actually be counterproductive.  In my article, I surveyed several meta-analyses of  the antioxidant vitamins A, C, and E — demonstrating a lack of benefit from supplementation, and in some cases positive harm.  At first, this result surprised me. How can one explain it?  After all, we know that vitamin-rich fruits, vegetables and herbs are good for us.  Extracts from these anti-oxidant-rich foods have been shown to neutralize reactive oxygen species (ROS) in the lab.  Hence, it must be the case that fruits, vegetables and herbs are good for us because of their antioxidant content – right?

Wrong. As we all know, correlation does not always imply causation.  And it turns out that fruits, vegetables and nuts may improve our resistance to oxidative damage for reasons other than their antioxidant content.  A more likely reason is that these foods are rich in polyphenolic phytochemicals–such as bioflavanoids– that stimulate the cells in our bodies to turn on a transcription factor called Nrf2, which activates our “xenobiotic” defense system.  This xenobiotic defense system or Antioxdiant Response Element turns on the production of a number of  endogenous anti-oxidant enzymes–such as superoxide dismutase and glutathione peroxidase–that inactivate ROS species catalytically.  That means that unlike the antioxidant chemicals in foods–which quickly get used up one-for-one when neutralizating oxidant molecules–the anti-oxidant enzymes turn over thousands of times, and are thus far more potent and sustainable defenses.  In addition, these enzymes are produced in cells throughout the body, localized where they are needed most.

In short, empowering our in-born antioxidant defense system is much more effective than supplementing with chemical antioxidants.

But what is even more startling is that supplementing with endogenous antioxidants can actually suppress your body’s endogenous ARE defense system.  Startling, but not too surprising once you realize that the ARE system is homeostatically regulated. That means that your metabolism compensates for external changes by making the appropriate internal changes in order to restore a rough balance.   Just as body temperature, blood glucose, and countless other internal variables are regulated, our defenses against oxidative stress are regulated.

Homeostatic regulation, ubiquitous in biology, evolved to help us adjust to changing circumstances, and to conserve resources. If antioxidants are supplied from the outside, there is less need to spend energy and internal resources making our own anti-oxidant enzymes, so the organism turns town their production. In my earlier article, I surveyed studies showing that this is just what happens, concluding:

So it appears that, by consuming more antioxidants, we become dependent upon them and perversely reduce our innate ability to detoxify. With any let-up in the constant supply of external defenses, we become more vulnerable to oxidative and inflammatory attack. And the externally supplied antioxidants themselves are in any case much less effective than the endogenous ones.

I ended by recommending that we select foods and herbs not for their anti-oxidant content, but rather for their hormetic ability to stimulate our native ability to produce’s its own detoxifying antioxidant enzymes. At the top of that list are brightly colored and bitter foods and herbs, such as broccoli, blueberries, red peppers, curcumin, green tea and even chocolate.

The moral of the story:  When possible, build your own capacity rather than relying on external supplies.

Now on to vitamin D.  Not everyone realizes that this “vitamin” is actually a hormone — a secosteroid in the same family as other steroid hormones like testosterone and cortisol.  As a hormone, the primary function of vitamin D is to regulate levels of calcium and phosphorus in the bloodstream, thereby promoting healthy bone formation.  But vitamin D also regulates a number of other important processes in the body, such as activation of both the innate immune system and the adaptive immune system.

The diet can supply vitamin D as either D2 (ergocalciferol, from plants) or D3 (cholescalciferol, from animals), but it is most effectively synthesized in the skin by the action of UV-B rays in sunlight acting on 7-dehydroxycholesterol.  (Yes, it all starts with cholesterol!).  But neither D2 nor D3 — the molecules present in supplements or food — are biologically active forms of the vitamin.  The diagram at right shows how vitamin D must first be converted by hydroxylation to calcidiol (usually designated as 25 (OH) D, or just “25-D”) in the liver and then further hydroxyulated to calcitriol (1,25 (OH)2 D or just “1,25-D”) in the kidney.  It is the 1,25-D form that is biologically active, binding to the vitamin D receptor (VDR) and activating a cascade of important biological functions, such as calcium absorption in the intestines.  So a well-functioning liver and kidney are required in order for vitamin D to be effective.

Vitamin D studies. Nobody doubts the important role of vitamin D in the body.  But are higher levels of a hormone like vitamin D–whether or not provided as a supplement– always a good thing?  Well, that is far from clear.  In a review of vitamin D studies in The End of Illness, David Agus, professor of medicine at University of Southern California, cites both positive and negative consequences of increased vitamin D levels.  On the positive side, a 2009 study presented by the Intermountain Medical Center in Utah, following 27,686 men older than 50 years over the course of a decade, found that those with the lowest levels of vitamin D had:

• 90% higher incidence of heart failure
• 81% higher incidence of heart attack
• 51% higher incidence of stroke

Pretty impressive association!  And yet Agus also cites two negative studies worthy of comment:

• A 2010 double-blind, placebo-controlled study, published in the Journal of the American Medical Association, found that older women who received annual oral high-dose vitamin D had an increased risk for falls and fractures.
• A 2008 study, published in the Journal of the National Cancer Institute, found that vitamin D does not reduce the risk of prostate cancer, and furthermore that higher circulating levels of 25-hydroxyvitamin D may be associated with an increased risk of more aggressive forms of prostate cancer.

Correlation vs. causation.  Agus points out that most of the vitamin D studies are “observational studies” that show associations. They uncover a correlation bertween vitamin D levels and some other condition. But they don’t show cause and effect. The few mechanistic studies of vitamin D action were mostly carried out in cell culture, for example adding vitamin D to breast cancer cell cultures suppressed their growth.  But in real humans, vitamin D is part of a homeostatic regulation system.  Vitamin D doesn’t just do one thing, like promote bone growth.  It is involved in as the regulation of as many as 2000 genes, turning up the expression of some, turning down the expression of others.

So how do we interpret these associations? As Agus points out, in regard to the Utah study:

An association, however, does not prove cause and effect. Another way of looking at this study is to say it’s quite possible that a heart condition lowers vitamin D levels, directly or indirectly— by keeping people with health challenges indoors and out of the sun. Also, obesity throws another wrench into the problem because excess fat absorbs and holds on to vitamin D so that it cannot be properly used in the body. Hence, is low vitamin D in this study just a marker for those who were obese? It’s the old chicken-and-egg conundrum. The same can be said for hundreds of other such studies that link the health (or lack thereof) of an individual to levels of vitamin D.

This is the key point:  Low vitamin D levels may be a biomarker for other problems.  It may be the consequence, rather than the cause, of certain conditions such as heart disease or obesity. For the same reason, high vitamin D levels may be a biomarker for good health.  Agus quotes Dr. JoAn Manson, chief of preventive medicine at Brigham and Women’s Hospital:

People may have high vitamin D levels because they exercise a lot and are getting ultraviolet-light exposure from exercising outdoors. Or they may have high vitamin D because they are health conscious and take supplements. But they also have a healthy diet, don’t smoke, and do a lot of the other things that keep you healthy.

If vitamin D level in the blood is merely a biomarker, a consequence of good or bad health, then adding vitamin D to the diet will not necessarily improve your health.  To really know whether vitamin D supplementation is beneficial, we need to look at interventional studies, where supplements are provided, and the outcomes are compared with those of control subjects who don’t get the supplement.  In fact the two above-cited studies on the effects of supplementation on bone fractures in older women, and prostrate cancer in older men are two such interventional studies.  And they showed that vitamin D supplementation was harmful in both cases.  And note that the positive Utah study I cited above–showing a correlation between low vitamin D levels and elevated incidence of cardiovascular disease and stroke–was an observational study, not an interventional one.  The men in that study with the higher vitamin D blood levels and lower incidence of heart disease were not given supplements.

Vitamin D levels are homeostatically regulated in our bodies, and this process varies with your genetics and health.  As one examlple of this, people with lighter skin color and less melanin in the skin evolved to make higher vitamin D levels even with reduced sun exposure; the converse is true of those with darker skin. (This may explain why African Americans are at much higher risk for vitamin D “deficiency”, particularly if they live in higher latitudes and work indoors).  People vary widely in the level at which they regulate vitamin D levels in their blood — it tends to be homeostatically controlled in a given individual, but the “normal” level may vary between 8 and 80 ng/ml, or even more widely than that.  Vitamin D levels are are genetically controlled by 3 or 4 genes, and are under control of the vitamin D receptor.  (This homeostatic regulation of vitamin D levels will sound familiar to those who read my previous post, “Change your receptors, change your set point“).  As Agus notes,

When your cells are deluged with vitamin D…they will pull back on their sensitivity to vitamin D by reducing their number of receptors for vitamin D. But if there’s a perceived shortfall of vitamin D in the bloodstream, your cells will up-regulate— create more receptors for vitamin D— to become more sensitive to every vitamin D molecule that passes by. What happens, then, when we consume lots of vitamin D from unnatural sources such as supplements? (I use the term unnatural to imply that it’s not coming from the sun, which is a source of vitamin D that has built-in regulatory mechanisms.) No doubt our bodies are adept at adjusting using their feedback loops as I just described, and the constant surplus of vitamin D means our cells are constantly down-regulating. If we took the supplemental vitamin D away, our cells would up-regulate to make up the difference. Vitamin D has multiple downstream signaling molecules, for the vitamin D receptor signals several reactions.

So if you take vitamin D supplements, and vitamin D is regulated homeostatically, your body will turn down its endogenous production of vitamin D.  If you believe that vitamin D is a “biomarker” of good health, do you really want to turn down the upstream processes that synthesize vitamin D?  Think about that before you pop a vitamin D capsule.

Unintended consequences.  Even worse, taking vitamin D supplements may actually suppress the immune system.  This “alternative hypothesis” of vitamin D has been put forward by Trevor Marshall and Paul Albert.  Supplementation with vitamin D will tend to increase levels of the inactive form of vitamin D–that is,  25-D.  Conversion of inactive 25-D to active 1,25-D in the kidneys is not immediate, and may not be efficient, particular if kidney function is less than optimal.  Now here is the problem:  While both the inactive 25-D and active 1,25 bind to the  vitamin D receptor (VDR), only the 1,25-D turns on the VDR, allowing it to perform its beneficial functions; the inactive 25-D actually inhibits the VDR.  This is a problem because the VDR is the “gate-keeper” of the innate immune system, regulating over a thousand genes. So elevated levels of 25-D can result in immunosuppressive effects.  As Albert writes in Vitamin D: The alternative hypothesis:

Indeed, the secosteroid 25-D may exert palliation on the innate immune system not unlike the way corticosteroids exert palliation on the adaptive immune system. So is it possible then that supplemental vitamin D is now perceived as a wonder substance simply because it effectively palliates the inflammation associated with diseases across the board? If so, this would certainly explain why its effects are most noticeable in the short-term and why efficacy often diminishes in the long-term.

And we need to also take into account the regulation of vitamin D levels through homeostatic feedback processes.  Consider that it is typically the 25-D form of vitamin D–not the biologically active 1,25-D– that is measured in blood tests.  And there is very little correlation between the active and inactive forms, as shown in the the figure below, from a 2009 study by Blaney et al., published in the Annals of the New York Academy of Sciences in a sample of 100 Canadian patients. As the authors note, while  many of the subjects had very low levels of 25-D–the type reported in most blood tests–most of them had levels of 1,25-D elevated above the normal range. Can those subjects with low levels of 25-D but elevated levels of the biologically active 1,25-D truly be considered vitamin D deficient?

Because low levels of 25-D are often associated with inflammatory conditions such as cardiovascular disease and autoimmune disease, people jump to the conclusion that low 25-D levels are a cause of the inflammatory condition.  On this point, listen again to Albert:

Yet, the alternative hypothesis must be considered – that the low levels of 25-D observed in patients with chronic disease could just as easily be a result rather than a cause of the inflammatory disease process. Our research suggests that this is the case. Indeed we have found that 1,25-D tends to rise in patients with  chronic disease and that these high levels of 1,25-D are able to downregulate through the PXR nuclear receptor the amount of pre-vitamin D converted into 25-D, leading to lower levels of 25-D.  I describe this finding further in my paper.  So are we really facing an epidemic of vitamin D “deficiencey” or are we simply beginning to note more signs of an imminent epidemic of chronic disease – an epidenmic which would be exacerbated by increasing the amount of vitamin D added to our food supply?

So the body is making enough active vitamin D to deal with inflammation–maybe even too much, leading to downregulation of the inactive 25-D precursor.  Trevor Marshall has also pointed out that elevated levels of 1,25-D may result from impaired activity of the  VDR, which is essential for innate immunity.  The excess 1,25-D can cause problems with other secosteroid receptors in the body, such as the thyroid receptor.  But adding more 25-D, beyond what is needed, will tend to only further inhibit the VDR, interfering with its beneficial anti-inflammatory actions, and impairing innate immunity.  In other words, well-intended supplementation with Vitamin D3 may actual backfire. Something to think about!

Marshall is currently conducting studies with a protocol involving restriction of vitamin D and use of an agonist drug that binds to the VDR receptor, upregulating it, and acting as an immuno-stimulant to treat immune disorders like arthritis and multiple sclerosis.  Marshall’s protocol is controversial, because it flies in the face of the orthodoxy about Vitamin D.  He acknowledges that vitamin D supplementation can indeed deliver some short term benefits because it acts as an immuno-suppressant–in much the same was as corticosteroids like prednisone. But just as prednisone is useful for acute treatments, yet is harmful if taken chronically, the immune-suppresant effects of vitamin D on the VDR may be detrimental.

One need not go to the extent of restricting or avoiding vitamin D to exercise some caution about actively supplementing it.  If supplementation has risks, is there anything you can do to ensure adequate levels of the active form of vitamin D?  Certainly, it is important to have at least an adequate level of D3 entering the liver, by eating foods rich in vitamin D,  and through biosynthesis from adequate exposure to sunlight.  But you also want to make sure that the conversion processes to 25-D in the liver and 1,25-D in the kidneys are functioning well.  Which means eating a low-inflammatory diet — that is, one that is low in sugars, processed omega-6 vegetable oils and other pro-inflammatory compounds.

Here is the takeaway from this vitamin D story, together with my earlier post about antioxidants: Inflammatory conditions, such as heart disease, infection or autoimmune disease are often associated with reduced levels of certain biomarkers in the blood,  such as antioxidant vitamins or hormones.  Our natural instinct is to conclude that these are “deficiencies” that need to be corrected.   While that may sometimes be the case, particularly in extreme cases, you should keep in mind the direct supplementation with additional vitamin or hormone may actually be counterproductive–by shutting down or impairing your body’s own ability to mount it’s own defense against oxidative stress and inflammation.

Rather than taking hormone and vitamin supplements, it is more effective to stimulate your body to strengthen its own defense and detoxification systems.  I’m not against all supplementation — for example, I believe that ingestion of phytochemical-rich vegetables and herbs is useful as a hormetic stimulus.  But I think we have to overcome the simplistic notion that if X is a good thing, we should consume more of X.

The body is more than a repository for chemicals — it is a self-regulating organism with hundreds of complex and dynamic feedback loops, evolved to enable us to adapt to changing circumstances and meet many challenges.  We should take care that what we ingest is used to build up our natural capacities, not subvert them.

February 11, 2013 update:  For suggestions on how you might be able to get the benefits of vitamin D supplementation without the possible downsides, see the more recent post:  An alternative to vitamin D supplements?

What an edifying and uplifting experience! We just wrapped up three days of excellent talks, panels, poster presentations and plenty of informal networking and socializing. This conference is really the hub of the Paleo movement. The emphasis was on the most recent developments in the scientific, cultural, political, and practical approaches to overcoming the contemporary health epidemics that derive from a mismatch between contemporary lifestyles and the biology of our evolutionary heritage.  The talks and panels were diverse, covering nutrition, cholesterol, cancer, immune health, farming, exercise, and many other topics.

My previous post of July 15 contains links to the webpage of the Ancestral Health Symposium, where you can read about its purpose and review the program of speakers and other presenters.  The conference certainly did not disappoint.

The program was composed of formal podium presentations, panel discussion and poster presentations. There were formal poster presentation sessions right after lunch on Friday and Saturday, where the poster presenters stood by their posters, provided a short overview, and then engaged in extensive Q&A. I liked this format very much because it maximized interaction and allowed me to meet many long time followers and newly interested people.  I was also able to continue discussions next to the poster throughout the day at various times.

Many of you who could not attend may be interested in learning more about my presentation and how it was received.

My talk was a very high level summary of what I’ve written about on this blog over the past two years.  It very well received and I was overwhelmed by the level of interest in hormesis.  My presentation started with a general overview of hormesis and a number of practical examples of how to apply it.  Since it would have been impossible to cover every application, I selected three to focus on:

• Calorie restriction and intermittent fasting
• Allergen immunotherapy
• Vision improvement

While there was interest in all of these topics, one topic in particular generated the greatest interest. Can you guess which one?

Vision improvement!

This was an audience that  was on the whole unusually physically fit, and there was intense interest in looking to the wisdom embodied in human evolution and pre-industrial and pre-agricultural society as a source of ideas for improved health.  Yet a significant number of attendees were wearing glasses — not exactly a “paleo” practice.   So there was acknowlegement when I pointed out that myopia is not in our genes, but has become prevalent because of environmental factors — primarily intensive schooling, near work and poor visual habits. (Many thanks to Otis Brown for the analysis and reference to the Eskimo study I referenced in support of this point). Yet there was shock — and intense interest — when I pointed out that myopia can be prevented and even reversed by the techniques I discuss in my blog.  Several of you discussed this with me and expressed a desired to embark upon a program to reverse myopia, and in some cases hyperopia or presbyopia.

I’m attaching here a link to a pdf copy of the poster.  Keep in mind that the actual poster size was 48″ wide by 36″ tall, so it does not fit on a normal computer screen. But you can easily adjust the zoom and use the arrows on your keyboard to scroll around, or print it out in a reduced size format if you have good eyesight:

Hormesis: A New Lens for Understanding Health and Improving Resilience

For those who have trouble reading the poster, or want an easier read, I present below the full text and set of images in the form of a standard blog article.  Most of the content will be familiar to those of you who have read this blog over the past few years.  But for those of you who are new to the topic of hormesis, I think it provides a good overview. I’ve also hyperlinked  to articles on a number of the topics that are discussed, for further reading.

____________________________________________________________________________

HORMESIS: A NEW LENS FOR UNDERSTANDING HEALTH AND IMPROVING RESILIENCE

Overstressed – or understressed?  What explains the recent pandemic rise in “diseases of civilization” like obesity, diabetes, cardiovascular disease, autoimmunity and cancer – conditions much less prevalent in ancestral populations?

One common answer is that contemporary life is too stressful. The prescription is to minimize exposure to certain chemicals, foods, UV, or psychological stress.  But stress is a double-edged sword.  While chronic or excessive levels of stress can indeed cause illness, so can a “deficiency” of stress.  Exposure to stress at the right intensity and frequency activates the body’s natural defense and repair mechanisms, improving health and resilience. The hardier life of our ancestors had benefits.

This poster presents the case for judicious application of progressive, intermittent stress to overcome conditions as diverse as obesity, addiction, depression, allergies and even myopia.

What is hormesis?  Hormesis is a  biological phenomenon whereby a beneficial effect (improved health, stress tolerance, growth or longevity) results from exposure to low doses of an agent that is toxic or lethal at higher doses.

The LNT (linear no-threshold) model of conventional toxicology assumes that toxic effects are inhibitory even at very low doses.  But many examples have been found of “hormetic” chemicals or stimuli with a “biphasic”  or “inverted U” dose response curve, illustrated below.  At low doses, the “toxic” or inhibitory agent actually becomes stimulatory or beneficial to the organism. [1]

Hormesis appears to work by activating endogenous defense and repair mechanisms found in all organisms, thereby improving resistance to stress and disease.

Examples of Hormesis

MECHANISMS AND APPLICATIONS OF HORMESIS

CALORIE RESTRICTION

Diets with calories reduced by 30-65% versus free feeding have been shown to extend lifetime and reduce degenerative disease in a wide variety of animals. [2].  What explains this?  Several proposed mechanisms have been demonstrated:

Autophagy: A cellular “recycling” process. Calorie restriction dramatically lowers the concentrations of insulin, IGF-1 and growth hormone, activating enzymes that degrade damaged intracellular macromolecules and use them for energy.

Mitohormesis: A defense response initiated in the mitochondria.  Calorie restriction turns on sirtuin genes that code for endogenous antioxidant enzymes and neurotrophic factors like BDNF, neutralizing reactive oxygen species (ROS), slowing the aging process, and protecting against neurodegenerative diseases like Alzheimer’s.

Receptor upregulation.  Brain scans in rats (below) show that after 3 months of restricted eating, D2 dopamine receptors in the brain are upregulated. [3]. This in effect lowers body fat “set point”. Calorie restriction also upregulates GLUT-4 and insulin receptors in muscle and liver.

Fasting and weight loss increase dopamine receptors [3]

Intermittent Fasting (IF). Fasting for 12-24 hours intervals per dayproduces similar health benefits as general calorie reduction, without activating a starvation response or risk loss of lean muscle.  A “cycling” approach may optimize the secretion of (and sensitivity to) hormones such as insulin, leptin, ghrelin, cortisol, and thyroid hormones.  For many, eating less frequently is easier than eating less at each meal; with time it naturally suppresses between-meal hunger. [4]

ALLERGEN IMMUNOTHERAPY

The allergy epidemic is frequently blamed on the profusion of pollutants and toxic man-made chemicals in modern industrial society.  But historical studies indicate allergies have become pandemic as our environment has become cleaner.

The Hygiene Hypothesis holds that inadequate exposure to allergens in childhood may be depriving our adaptive immune system from developing properly, failing to develop normal tiers of IgG, IgA and IgM antibodies.  The undertrained immune system tends to rely on the “emergency” IgE system, resulting in allergic response when confronted with normally harmless foreign bodies like pollen, dog hair, or peanuts. [5]

How to eliminate allergies. The conventional advice given to allergy sufferers is to avoid exposure to allergens and use antihistamines. Allergen immunotherapy takes the diametrically opposite approach:  Patients are given tiny amounts allergen in shots or sublingually.  Exposure is then slowly increased in a systematic way.  The emergency IgE response is thus dampened by stimulating production of an allergen specific IgG that blocks the IgE response and modulates the helper T cell response.  Allergen immunotherapy has reversed allergies to peanuts and other foods in children. [6]

VISION IMPROVEMENT

Is myopia a result of nature or nurture?  While certain populations may be genetically predisposed, studies show that nearsightedness is tied to environmental factors like increased schooling and close work.  A multi-generational study of a Eskimos revealed a statistically significant downshift in mean refractive state, from +1.8 diopters (hyperopic) in the older (unschooled) generation to -2.1 diopters (myopic) in the younger (schooled) generation. [7]

The Incremental Retinal Defocus Theory (IRDT) provides a plausible explanation for myopia induced by near work. [8] Effort by the retina to focus on near objects slows the rate of retinal neuromodulator proteoglycan synthesis in scleral tissues, causing axial elongation of the eye.  Repeated cycles of “near work” induce axial growth that leads to permanent myopia. This has been further confirmed in studies of chicks and other animals in which axial elongation and myopia could be rapidly induced or reversed by respectively fitting them with plus or minus lenses.

How to reverse myopia.  Conventional “correction” of myopia by fitting the eye with concave (minus) lenses provides short term relief, but at the cost of inducing progression of the underlying myopia. It is as futile as trying to “strengthen”  a weak leg by prescribing crutches.

Anti-corrective lenses are the hormetic solution.  Myopia is reduced by inducing a slight myopic defocus or “underaccommodation”. This can be done using reduced prescription minus lenses for distance viewing, and using plus lenses (or the naked eye) to read text at the “blur point” – the maximum distance beyond which the printed word just begins to blur. [9]

Myopic defocus induced by a convex (+) lens on a myopic eye. From DeAngelis [9], p. 38

THE BLOG:  HORMETISM

Getting Stronger is a blog about the philosophy of Hormetism, based on the application of progressive, intermittent stress to overcome challenges and grow stronger physically, mentally and emotionally.

Some popular blog posts:

• Cold showers
• Improve eyesight – and throw away your glasses
• Intermittent fasting for health and longevity
• Does insulin make you fat?
• Change your receptors, change your set point
• Obesity starts in the brain
• How to break through a plateau
• The paradox of barefoot running
• The case against antioxidants
• A cure for insomnia?
• Overcoming addiction

My presentation at AHS 2012 will be about the role of hormesis in optimal health. 

UPDATE:  Here is a link to the poster sessions – scroll down to see the full abstracts and biographies.  You’ll see my talk and abstract listed there:

AHS 2012 Poster Sessions

The Ancestral Health Symposium is considered by many to be the “Woodstock of Evolutionary Medicine”.  According to the Ancestral Health Society website, this annual event “fosters collaboration among scientists, healthcare professionals and laypersons who study and communicate about health from an evolutionary perspective to develop solutions to our modern health challenges.”

This year’s Ancestral Health Symposium will be only their second annual meeting.  Last year’s inaugural meeting was the buzz of the paleosphere, featuring a long list of paleo luminaries familiar to readers of this blog, including:  Loren Cordain, Mark Sisson, Robert Lustig, Gary Taubes, Seth Roberts, Robb Wolf, Stephan Guyenet, Michael Eades, Denise Minger, Chris Masterjohn, Doug McGuff, Erwan LaCorre, Tom Naughton, Richard Nikoley, J. Stanton, Emily Deans and others.  AHS 2011 was informative, exciting and featured both formal and informal debate and even controversy.  For a great synopsis of last year’s meeting, here are a few good review posts:

• Chris Masterjohn
•  J. Stanton
• Neely Quinn
• Kyle Knapp
• Richard Nikoley

This year’s roundup promises to be equally impressive.  Take a few minutes to look at the program,  speakers, and poster presenters, as well as details on how to attend:

• AHS 2012 program and application to attend

If you are interested in attending, my understanding is that tickets are moving fast and are likely to sell out.

If you plan to be there, I’d like to meet you; send me a note using the contact form at the right of the blog page.

Todd

The article has generated a lot of interest, but also some skepticism.  People who otherwise recognize that weight lifting can remodel muscles and diet can change metabolism fail to appreciate how the same principle of gradually applied stimulus can change the focal range of the eye. Since I wrote the article, many contributors to the Discussion Forum have chimed in with their progress, their questions, and their success stories.  Quite a few individuals have been able to significantly reduce the strength of their optical prescriptions.  In a few cases, they have been able to return to 20/20 vision, or better.

Sometimes real success stories can inspire us to try a new approach.  So I invited one of our Forum members, who goes by the screen name “Shadowfoot”, to share his story with you.

Todd: Thanks for volunteering to do this interview, Shadowfoot.  For the benefit of readers, please tell us a little about yourself.

Shadowfoot:  I’m seventeen years old, and I live in the United States. I like to think that I have had an eclectic upbringing, and I suppose that is at least partially true. I have been home-schooled, public schooled, gone to a Montessori school, and will earn my associates degree from the local community college this Spring, in addition to being highly self educated. In many ways, you might say that I am not a typical teenager. Yet I also think that in other ways I am much more of a teenager than I would like to admit.

Todd:  Your passion and your motivation are evident in your contributions on our Discussion Forum, Shadowfoot. Tell us about how you came to start wearing glasses or contacts and how it progressed. What caused you to question the wisdom of continuing to wear corrective lenses?

Shadowfoot:  I’ve had imperfect vision for as long as I can remember. Even before I got glasses, I was often unable to read signs at the same distance as those around me. The distance which I was able to read signs was probably two to three times normal or so, at least in the years before I got my glasses. Yet it did not negatively impact my life in any major way, so I didn’t really see any need to get glasses. That changed a few years ago when I began to have trouble reading the whiteboard in school. It was then that I decided to get glasses.

Todd:  What was your initial reaction to wearing glasses?

Shadowfoot:  I remember that wearing them always gave me a feeling of power and satisfaction. There seems to be a human fascination with improving very quickly. A perfect example is the endless range of “Learn X in two weeks” products. Glasses are what these products wish they could do. They are what drugs wish they could do. “Here, put these on . . . and now you are perfect.” Basically, I could see SO much better. Imagine if you could put on a pair of shoes and run two times faster. That’s a little bit like how I felt.  So for a year, I wore glasses to school and when travelling, but not around the house or when reading. Sometimes I did, but I generally shied away from it for a different, and very important, reason: I seem to have a natural aversion to wearing things. For example, I am always happier in the summer in loose fitting clothing and no shoes. In the same way, despite the amazing vision, I did not like to wear glasses when they were not necessary.

Todd:  I had the same attitude.  I really did not like having to wear glasses.

Shadowfoot:  Yeah.  So I was caught between two ideals: the desire to have perfect vision and the desire to not wear glasses. One night, about two years ago now, in a fit of boredom, I turned to Google for an alternative. I quickly discovered the Bates Method. Despite that fact that it was labeled as pseudoscience and most of the sites I found talking about it seemed to be trying to sell me something, the allure was too great. I learned the basics and had some success over the next year.

Todd: Where did your vision start out when you came across the Bates Method and how did you progress from there?

Shadowfoot: When I first wore glasses, I was at 20/40, as confirmed by the Snellen chart in my biology lab. When I found your site, after a year of not wearing glasses, I was down to 20/30. I attribute that to Bates’ method of distance gazing and relaxation techniques. I don’t think the eye strengthening exercises such as making figure-eights with my eyeballs helped much though.

It was not until I discovered the plus-lens method and really began to experiment that I was able to improve my vision to the level I desired.  After six months of further experimenting, I reached 20/15. Presently, depending on what kind of work I have been doing and how diligent I have been about proper habits, I generally fluctuate between 20/20 on a good day and 20/25 on a bad day. In the future, I hope to reach 20/12, which I have reason to believe is my maximum possible acuity. But that’s not so much a matter of technique as diligence. It’s like, I could break the five minute mile mark and shave off those last twenty-three seconds from my personal record. But I just . . . haven’t. I don’t really have any need to. Unless I am feeling ambitious, 20/20 vision is usually “good enough.”

Todd:  I think getting from 20/40 to 20/20 is quite an impressive improvement in less than a year!

Shadowfoot: I suppose. I could probably get back to 20/15 or better in a few weeks if I was really diligent about it. At the same time, I could just as easily drop back to 20/40 in the same amount of time if I wanted to. That’s why it’s all about persistence over the long term.

Todd: You’re definitely right about that. Vision improvement is not a one-time effort. It’s about maintaining good vision with good practices. But I’d like to know more about your success.  Can you expand upon your experience?  What tips can you share about what worked well for you?

Shadowfoot: Before I answer that, I want to say a few things about the causes of myopia. Hopefully, this will help to clarify my methods and observations.

Todd: Sure, go ahead.

Shadowfoot: The powerful realization that I have come to is that there are actually two mechanisms by which myopia occurs. The first is an actual physical elongation of the eyeball. This causes light to fall before the retina, resulting in a refractive error. The second kind is caused by the eye remaining accommodated to close work even when viewing in the distance. Here the optics are a little bit more complicated, but the end result is the same. I think this accommodative myopia is related to sustained muscle tension rather than changes to the shape of the eye.  So it is much quicker in the onset, as well as the relief. It is this instability that probably causes the daily swings in vision often observed and noted on your forum. My approach has been primarily to minimize accommodative myopia, while at the same time slowly improving the true myopia aspect.

Todd:  Yes, I think that what you call “accommodative myopia” is sometimes called “pseudomyopia”.  It’s quite real, but unstable.  So how did you deal with that?

Shadowfoot:  I do a number of things. When reading, I try to give my eyes frequent breaks, even if it is only looking into the distance for a few seconds, and by making a habit out of distance gazing several times a day. I do this by tracing objects in the distance, such as tree branches or telephone lines, sometimes bare-eye and sometimes with plus lenses. They both seem to have advantages. And when I do that, I generally try to trace objects: the edges of houses, trees, etc, which I find more effective than just trying to “look” at things. Actually, just looking at things doesn’t really work at all, because your eye will tend to rest on things it can see well. That’s why you have to challenge the limits of your acuity. This has two purposes: first, to stretch and relax the eye muscles (essentially combating accommodative myopia); and second, to challenge my visual threshold, which is, ultimately what causes vision improvement. When I do these things, my vision improves, when I don’t, it flatlines or gets worse. Yet, I have a tendency to get absorbed in what I am doing and forget to do this. Haven’t figured out how to beat that one yet.

Todd:  I also like to do what you suggest – alternating my focus between near and far objects, and carefully observing the sorts of details and features you mention.  You make an excellent point that vision improvement is an active process.

Shadowfoot: There is something else I feel the need to point out, although it is a little hard to explain. When doing the exercises I just mentioned, I sometimes feel a kind of tension in my eyes, particularly if I have recently been doing a ton of reading without any breaks. Tension isn’t really the right word, because, to the best of my knowledge at least, I am actually relaxing the eye muscles. The best analogy I can think of it when you have been sitting for too long and you stand up. There is a period of time when your muscles suddenly feel tight in their new positions, as if they still want to be sitting. It is a little bit like that. So, in general, when doing these exercises, I try to go slowly if I feel any of this so-called tension, making sure to relax my eyes often by closing them for a few seconds.

There is also another kind of tension related to working at the edge of your optical range, either when using the plus lens or distance gazing. There was a whole episode I described on the Forum, when I discovered that tension, specifically from using the plus lenses too much, was causing me to get redeye. For that reason, I generally don’t use the plus for close work anymore. Distance gazing is generally less intensive and for shorter periods of time, so I don’t have a problem there.

Todd:  Yes, a number of people on the Forum have mentioned problems like eyestrain and redeye.  I agree with you that it is important to take breaks and rest.  Pushing too hard is counterproductive.

Another question:  Do you still wear glasses – either minus lenses or plus lenses?

Shadowfoot: I haven’t worn minus lenses in two years, except when I want to give myself motivation. A sort of, here is what you have to look forward to, why are you being lazy? But then it is only for a few minutes, as the prescription doesn’t fit anymore and they give me a headache pretty quickly. As for plus lenses, I like going for walks in the woods with those. But I don’t use them for close work.

Todd:  Thanks for the good discussion, Shadowfoot.  I hope your success will inspire others to take charge of their vision and take a closer look at how you, I and others have reversed our myopia and overcome our dependence on wearing glasses.

To my readers:  If you want to know more about how Shadowfoot and others improved their vision using the principles of hormetic stress, I strongly encourage you to read the thread called “Eyesight without Glasses” on the Rehabilitation page of the Discussion Forum of this blog.  Many questions you may have are already answered there. Feel free to post your questions and share your experience there.

September 6, 2012 update:

This blog article is now CLOSED to further comments. I think it has gone on long enough. If you wish to comment further or raise additional questions, please do so on the Discussion Forum linked to this blog.

Thanks,

Todd

Yet Wim is not a genetic freak or Tibetan monk. He is a 52 year old Dutch man without much body fat. He believes that anyone can adapt to the cold and learn to control body temperature.

In this article, I will try to answer two questions:

• How does he do it, and can anyone really do the same?
• Is this basically an impressive stunt, or is there any benefit to learning Wim’s methods?

No stunts.  First, just to be clear about what Wim has been able to accomplish,  take a look at these two short videos:

1. Wim running a half marathon in the north of Finland:

2. Wim swimming 50 meters under arctic ice:

An enjoyable account of Wim’s remarkable adventures and methods is detailed in the book Becoming the Iceman, co-authored by Wim Hof and Justin Rosales.  Rosales is a college student who became so intrigued with Wim’s abilities that he managed to earn enough money washing dishes–while still attending classes–to travel to Europe and learn Wim’s methods.  The chapters alternate between those written by Wim and those by Justin. While their account suffers from a lack of editing and is sprinkled with grammatical errors, the excitement of Wim’s remarkable sense of fearless adventure and Justin’s learning process make this book a real page-turner.

Changing how body temperature is regulated.  How does Wim Hof manage to keep his core body temperature elevated, maintain peripheral circulation, and avoid frostbite and hypothermia?  Nobody knows for sure, but there is no doubt that he does it.  Dr. Kenneth Kamler, an expert on hypothermia, frostbite and high-altitude medicine, who has himself climbed up Everest, has observed that Wim’s trained body responds differently than yours or mine.

The normal response to extreme cold exposure starts in the peripheral blood vessels in the extremities  – the ears, nose, fingers and toes.  Blood flow in the extremities at first increases, in order to stimulate warming.  If the cold exposure is prolonged more than a few minutes, goosebumps and shivering kick in to induce warming of muscles and skin.  But if the exposure continues beyond that, a process of biological “triage” takes place.  To preserve the high priority  organs – brain, heart, digestive tract — the body shuts down blood flow to the extremities to prevent further heat loss. The peripheral veins snap shut to segregate warm interior blood from cold peripheral blood. After all, these extremities have a lot exposed surface area, so cutting them off greatly conserves heat.  But the cost of doing this is frostbite and the irreversible tissue damage that often results if the cold exposure is sustained for more than a brief time.  Finally, when the core temperature falls below 95 F, the various stages of hypothermia set in, ultimately leading to death if sufficiently prolonged.

But Wim, and Tibetan practioners of the ancient art of Tummo, are able to significantly alter this normal process.  As Kamler explains, the key adaptation occurs within the brain during meditation–specifically the yoga and controlled breathing exercises that Wim and the tumo practitioners follow.  Of these exercises, breath retention exercises are key.  As a result, there is a significant activation of blood flow and electrical activity in his frontal cortex and hypothalamus — areas that regulate peripheral nerves and veins involved in the regulation of body temperature.   Normally, the circuit between the hypothalamus and these temperature control circuits is involuntary, governed by the autonomic nervous system. Kamler reasonably speculates that,  through meditation, Wim is able to override the normal function of the hypothalamus, allowing the peripheral veins to remain open and heat the extremities, preventing injury.  He points out that Wim must be generating heat and distributing it more efficiently, but he admits having no idea mechanistically how Wim’s meditative techniques accomplish this.

The monks who practice Tummo are able to tolerate cold, but they do so in a meditative pose, while sitting. They speak of being able to generate an “inner fire”.  Wim Hof’s method has diverged from that of classical Tummo. He has innovated significantly, since he is able to control his body temperature while moving about, in fact while exerting himself under conditions of running, swimming, or high altitude climbing which would be challenging for most people even at ambient temperatures! Yet, while Wim is certainly a one-of-a-kind personality, he is insistent that anyone can apply his techniques. His success in teaching Justin Rosales and others seems to bear that out. More recently, Wim  has devoted himself to training others through seminars and training expeditions.

Other abilities.  Wim’s ability to voluntarily control what what we consider to be automatic, involuntary responses does not stop at tolerance of extreme cold.  He has also learned to tolerate extreme heat, consciously overcome pain and cramping, and even moderate his immune response to endotoxin.  A fuller discussion of these abilities is given in Becoming the Iceman.

Possible benefits.  I’m particularly interested in Wim Hof, because of my own positive experience taking daily cold showers.  As I discussed in my post, Cold Showers, making a daily habit of cold showering results in a remarkable degree of adaptation.  The initial intense discomfort of cold shock rapidly shrinks in both intensity and duration, and the self-heating process of thermogenesis becomes more prominent after only a few weeks of the daily habit.  I’ve found benefits in weight control, mood enhancement, and generalized stress resistance.  I’ve not had any colds since starting cold showers. When my family was suffering with a stomach flu that lasted several days, the net effect on me was a 12 hours of achiness which I slept off on a single night, with none of the nausea that they had.

Could more aggressive exposure to the cold provide benefits that go beyond that of daily cold showers?  Hof and Kamler have suggested that the ability to open up peripheral veins and capillaries may help to enhance more than just temperature regulation.  It likely improves blood circulation overall, particularly in the smaller peripheral vessels. Because there are so few individuals that do what Wim Hof does, there is not yet any body of clinical science regarding the benefits to circulation.  But it is not hard to speculate that cold exposure could be a great way to fend of a wide range of cardiovascular and circulatory maladies.  So it intrigues me.

Total cold water submersion.   Cold showers are great, but what Wim Hof does is far more extreme.  Not only is the temperature of the water significantly colder — 32 F vs. the 55-60 F of my showers — but the total body immersion involves much more extensive skin surface area contact, meaning more rapid heat loss. A few times a year, I go for a brisk 10 minute swim in the ocean.  Here where I live in northern California, the ocean temperatures range between 53 and 60 F, similar to my shower water, and ocean swims are definitely more bracing than the cold showers.

My first experiments.  I want to see if I can up the game beyond cold showers. I first read Tim Ferriss’s account of cold water exposure in his book, The 4-Hour Body.  In his chapter “Ice Age”, he recounts the method of Ray Cronis, a NASA scientist who was able to lose almost 30 pounds of fat — fat, not weight — in 6 weeks, by taking cold walks, cold swims, and by drinking cold water.  Ferris himself tried immersing himself in cold baths — with added ice — for 20 minutes.  But he first heated himself to the point of sweating by consuming a thermogenic cocktail of ephedrine, caffeine and aspirin.  So what Conise and Ferris did doesn’t really approach the level of unmediated cold exposure undertaken by Wim Hof.

I want to see how much I can directly adapt to the cold.  My first effort will be to attempt this without any special meditative technique or breathing method, and certainly without taking any thermogenic medications or supplements, as Ferriss did.  So I did my first experiment today, and here is what I did and what I experienced:

I filled a bath with cold water, which I measured at 58 F (14 C).  I first submerged my legs.  It was painful, so I decided to allow myself to adjust before filling the tub with more water. Fortunately, after about 2.5 minutes, my legs no longer hurt and by 4 minutes they felt a kind of paradoxical warmth and I could wiggle my toes again. So I filled the cold water up to my chest when laying back. I was completely submerged at 9 minutes.  At first, this was very uncomfortable, and I started shivering. I felt some numbness, but that went away and I was comfortable again at  14 minutes. I could easily flex my toes and fingers. I continued laying in the tub, submerged up to my neck. The sensation alternated between shivering and coolness. I stayed in until 20 minutes had passed from the initial plunge.

After I got out of the bath, I felt warmer and tingly at first. But 5 minutes after getting out and drying off, I started feeling very cold and shivering uncontrollably. I was not really expecting that; I thought I would instantly feel warmer, just as I always do after stepping out of a cold shower. But in the book Becoming the Iceman, Justin Rosales and Wim Hof describe a phenomenon they refer to as “the afterdrop”, an experience of getting colder after you emerge from cold water. This is exactly what was happening to me. I needed to  put on warm clothes and move around to fight off the shakes. I was still cold and shivering 30 minutes after emerging from the cold bath, and my fingers were stiff, making it hard to type up my notes.

However, a full hour after finishing the bath I started to feel great. I became warmer throughout the evening, even though it has been a chilly evening. Psychologically, I have been quite alert all evening long. So there is some evidence of adaptation, even though the experience has been quite different than what I would have predicted from my familiar habit of cold showers.

I plan to continue experimenting with cold baths over the coming weeks, varying both the duration and the water temperature.  I’m interested to see how readily I adapt, and what other benefits or problems occur along with the adaptation.

Our drives are largely governed by two small primitive brain structures, the hypothalamus and the amygdala – shown in red in the drawing at right.  Remarkably, these two tiny structures are respectively the size of a pea and an almond — representing less than 1% of the brain’s three pounds of neural matter. Together, they constitute the control center of the paleomammalian brain–the “limbic” brain that governs our basic urges and desires as well as our homeostatic “set points” for temperature, sleep, body fat and behavioral urges like sex drive and aggression.

You can attempt to change your behavior by conscious determination and cognitive therapies.  But most attempts at intentional change are temporary and are doomed to fail in the long term because they are strongly resisted by powerful homeostatic processes encoded in our limbic brain.  Modern medicine recognizes the importance of homeostatic drives, and has developed pharmaceuticals to override them with diet pills, sleeping pills and antidepressants.  In fact, these medications do shift the balance of neurotransmitters and neural activity — at least in the short term.  But such chemical interventions are short-sighted “crutches” that promote dependency and come with side effects.  Often they exhibit  a “tolerance” effect: the brain’s control system fights back and weakens the impact of the medication.  To maintain the benefit, doses are increased, but this strategy may not always work.

This article will explain how the hypothalamus and amygdala contribute to the regulation of basic drives like eating, sleeping and sexuality, and how the amygdala can actually override the hypothalamus by enhancing the reward value of foods and other stimuli. (As I will explain, however, my take on “food reward” is different from that of Stephan Guyenet and other advocates of the Food Reward Hypothesis). This dual-control model can help explain anomalies such as obesity, addiction, and disordered sleep.

Finally,  I will provide suggestions on effective and natural ways to re-program the hypothalamus and amygdala and change your homeostatic set points, using the principle of hormesis.

Hormesis. Readers of this blog are familiar with hormesis:  a biological process whereby a beneficial effect (improved health, stress tolerance, growth or longevity) results from exposure to judicious doses of an agent that is otherwise detrimental at higher doses.  The many examples of homesis we’ve discussed on this blog involve adaptations that roughly fall into three categories.  The first two categories are quite well-known:

Structural adaptations to organs and tissues:

• Muscular growth, from weight lifting
• Adaptations of the foot and leg, from barefoot running
• Reversal of myopia, from use of anti-corrective lenses
• Other examples: calluses, suntanning

Defensive adaptations against foreign subtances:

• Immunotherapy to overcome allergies
• Endogenous defenses against oxidants and “xenobiotic” toxins

The third category is perhaps a less well recognized form of hormesis:

 ”Psycho-metabolic” adaptations:

• Hormonal and enzymatic adaptations to caloric restriction and fasting
• Psychological and weight loss benefits of cold showers
• Cue exposure therapy to overcome addictions
• Sleep restriction therapy to counteract insomnia

Psycho-metabolic adaptations. Let’s now expand upon this third category of adaptations, focusing on how certain types of stimulus or “stress” can bring about long term changes within the brain’s control system — the hypothalamus and amygdala.  These adaptations can induce broad sets of changes to your metabolism and psychological functioning.   These changes are long term adaptations — to be distinguished from short term or “artificial” changes that can temporarily induce weight loss, boost metabolism, energy level, wakefulness, or sex drive.   A true change in “set point” requires a sustainable physiological change that is reflected in real alterations in neuron density or receptor sensitivity within the brain.  In turn, these changes to the brain result in systemic changes elsewhere in the body.

In previous posts, I’ve touched upon a few topics that relate to the general thesis of psycho-metabolic adaptations that involve changes to the brain:

1. In “Change your receptors, change your set point“, I presented evidence that individuals suffering from obesity, addiction and depression have in common a down-regulation (reduction in the number or sensitivity) of dopamine receptors. In depression, receptors for other neurotransmitters such as serotonin are also down-regulated, a problem that can actually be made worse by chronic use of SSRI antidepressants.  The article also summarized research indicating that intense exercise, caloric restriction and intermittent fasting can up-regulate dopamine receptors and thereby provide a sustainable treatment for certain types of obesity, addiction and depression.
2. In  ”Obesity starts in the brain“, I outlined the Hypothalamic Hypothesis, a brain-centric analysis of obesity.  I argued that there are two different types of obesity–intra-abdominal and subcutaneous obesity–and that these conditions respectively result from  impairments to the insulin sensitivity or leptin sensitivity of a specific part of the hypothalamus — the arcuate nucleus.  Furthermore, it is the hypothalamic impairments that are primary; for example, insulin resistance starts in the brain and later spreads to the liver and muscles.  The article pointed to specific dietary and inflammatory factors that can improve hypothalamic sensitivity to these hormones and reverse obesity.

I will now build upon the Hypothalamic Hypothesis to account for the influence of the amygdala, to consider how the limbic system governs for drives other than eating, and to propose more generally how we can influence the brain’s control system.

The limbic system. Think about this:  By weight, about 85% of the human brain is the elaborate cerebral cortex, devoted to complex perceptual and conceptual processing and executive function.  In contrast, only a tiny piece of the brain is responsible for the full gamut of motivational drives and emotions, and for maintaining the balance of homeostatic functions like metabolism, body temperature, sleep and energy level.  The simultaneous management of all of these diverse functions is tightly packed into two nut-sized structures–evidently without getting signals crossed! When you think about it, this fact is quite astonishing.  It baffles me that, despite great popular interest in neuroscience, there has been so little commentary about this striking fact.

You can think of the the massive cortex as merely an elaborate pattern recognition system wrapped around the limbic brain.  The cortex’s pattern recognition system has evolved to improve the quality of information being fed to the tiny thermostatic hypothalamus and amygdala.  While the cortex gives us a huge advantage over other animals in analyzing our environment, we seem not to exert much real control over basic drives like eating and sleeping.  Despite the evolutionary achievement of “rationality”, we humans remain to a large extent at the mercy of our basic animal drives and emotions.

Things are not so bleak, however, once we recognize what makes the limbic brain tick.  While we may not have direct volitional control over the limbic system, there are actions we can take to influence the balance of neural forces within the hypothalamus and amygdala. Over time, we can literally reprogram our psycho-metabolic control systems.

But first a little anatomy.   And I’ll try to keep things simple.  The point of this interlude is not to teach anatomy, but rather to highlight a few key parts of the limbic control system and how they function. I’ve borrowed much of the following discussion from the excellent and incisive monograph, The Limbic System, by Rhawn Joseph, much of which is also contained in Chapter 4 of his online Brain e-book.

The figure below provides a “macro” view of the major parts of the limbic system.  Located at the center of the brain, perched atop the brainstem, the limbic system includes not only the hypothalamus and amygdala, but other structures such as the hippocampus, cingulate gyrus, pituitary gland.  But particularly note that the amygdala is connected tightly by numerous nerve bundles to the hypothalamus.  The amygdala acts directly on the hypothalamus to control hypothalamic drives, and conversely, the hypothalamus “uses” the amygdala (and to some extent the septum) as a window on the world to satisfy its drives by selectively searching out appropriate foods, potential mates, and sleep and exercise opportunities.

Furthermore, notice that the amygdala is closely connected to the olfactory bulb, and mediates its connections to the hypothalamus.  As Joseph notes, “The hypothalamus is exceedingly responsive to olfactory (and pheromonal) input. Perhaps reflecting this partial and putative olfactory origin is the fact that this structure utilizes chemical (hormonal, humoral) molecules to communicate with other areas of the brain, and reacts to these same molecules as well as olfactory cues, including those directly related to sexual status.”  We will come back to the under appreciated importance of olfactory cues in the limbic system’s control of basic drives, particularly appetite and sexual/social attraction.

For present purposes, there are four important points to understand about the actions of the hypothalamus and the amygdala:

1. The hypothalamus is purely reactive. The hypothalamus regulates drives, but is almost totally “blind” to the outside world.  It is inwardly focused and responds reflexively.  It has no memory and acts “in the moment”.   According to Joseph, the hypothalamus is the physical embodiment of the Freudian id:

Emotional functioning at the level of the hypothalamus is not only quite limited and primitive, it is also largely reflexive… Emotions elicited by the hypothalamus are largely undirected, short-lived, being triggered reflexively and without concern or understanding regarding consequences; that is, unless chronically stressed or aroused. Nevertheless, direct contact with the real world is quite limited and almost entirely indirect as the hypothalamus is largely concerned with the internal environment of the organism. Although it receives and responds to light, it cannot “see”. It has no sense of morals, danger, values, logic, etc., and cannot feel or express love or hate. Although quite powerful, hypothalamic emotions are largely undifferentiated, consisting of feelings of pleasure, unpleasure, rage, hunger, thirst, etc….it tends to serve what Freud (1911) has described as the pleasure principle. Functionally isolated, the hypothalamus at birth has no way of reducing tension of mobilizing the organism for any form of effective action. It is helpless. When tensions associated with immediate needs (e.g. hunger or thirst) become unpleasant the only response available to the hypothalamus is to cry and make rage-like vocalization. When satiated, the hypothalamus can only respond with a feeling state suggesting pleasure or at least quiescence.

2. The hypothalamus operates through a hierarchy of channels.  The hypothalamus receives information about the state of the organism, and in turn sends “commands”,  through three main channels:

• The bloodstream. Many signals are exchanged through the relatively porous blood-brain barrier.  For example, as discussed in my previous post on obesity, the hypothalamus receives and integrates a range of signals about short term nutrient status (glucose and fatty acids), gut signals (ghrelin, PYY and CCK) and longer term energy storage  (hormones like insulin, glucagon, leptin and adiponectin).   The blood also carries similar signals regarding body temperature, wakefulness and sleep, and state of readiness for action. And the hypothalamus activates the section of neuroendocrine activators via other glands like the pituitary, thyroid and adrenal glands.
• Nerve fibers –”afferents” and “efferents”.  Certain communication is done via nerve fibers. For example, appetite cues are provided from the nose via the olfactory bulb and from the gut via the vagus nerve.  Body temperature cues are provided from remote thermoreceptors.  The sleep-wake cycle is calibrated by neural inputs from the suprachiasmatic nucleus (SCN), which responds to dark and light cycles.  And conversely, the hypothalamus uses efferent nerves to remotely regulate adrenal glands and digestive organs.
• Higher order inputs.  The above chemical and neural inputs can be modulated or overridden by “emotional” interpretation of perceptual and cognitive inputs.  This is is where the amygdala comes in.

3. The amygdala is the “handmaiden” of the hypothalamus.  It serves as the emotional eyes and ears for the hypothalamus by translating the input of the senses and the great pattern recognition capability of the higher cortex into emotional responses that feed into the hypothalamus.  Going beyond the undifferentiated, spur-of-the moment emotional drives of the hypothalamus, the amygdala provides a highly selective response to specific and often complex sensory stimuli.  As Joseph explains:

In contrast to the primitive hypothalamus, the more recently developed amygdala (the “almond”) is preeminent in the control and mediation of all higher order emotional and motivational activities. Via it’s rich interconnections with various neocortical and subcortical regions, amygdaloid neurons are able to monitor and abstract from the sensory array stimuli that are of motivational significance to the organism. This includes the ability to discern and express even subtle social-emotional nuances such as friendliness, fear, love, affection, distruct, anger, etc., and at a more basic level, determine if something might be good to eat.  In fact, amygdaloid neurons respond selectively to the flavor of certain preferred foods, as well as to the sight or sound of something that might be especially desirable to eat  including even the sight of drugs that induce extreme pleasure…Belying its involvement in emotion, including the pleasure associated with cocaine usage, is the unique chemical anatomy of the amygdala, which is rich in a variety of neuropetides including enkephalins and beta-endorphins as well as opiate receptors. In fact, of all brain regions, the greatest concentration of opiate receptors is found within the human amygdala.

Beyond appetite, the amygdala also provides a selective filter on sensory cues related to other drives such as sociality and sexual attractiveness.  Of significant note, the amygdala is the arbiter of very specific social cues such as facial recognition:

The amygdala is exceedingly responsive to social and emotional stimuli as conveyed vocally, through touch, sight, and via the expressions of the face . In fact, the amygdala, as well as the overlying (and partly coextensive) temporal lobe, contains neurons which respond selectively to smiles and to the eyes, and which can differentiate between male and female faces and the emotions they convey. For example, the left amygdala acts to discriminate the direction of another person’s gaze, whereas the right amygdala becomes activated while making eye-to-eye contact …Moreover, the normal human amygdala typically responds to frightened faces by altering its activity, whereas injury to the amygdala disrupts the ability to recognize faces. With bilateral destruction, emotional speech production and the capacity to respond appropriately to social emotionally stimuli is abolished.

Maybe this explains why Seth Roberts observation that looking at faces in the morning makes people happy–a simple anti depression therapy!

Joseph also notes that “The relationship between hypothalamus and amygdala is bidirectional.  The amygdala interprets sensory information and emotions and passes these inputs on to the hypothalamus to initiate drives. And when a drive like hunger or sex emerges, the amygdala helps out by surveying the environment for suitable choices of food or potential sexual partners.”

4. The hypothalamus and amygdala  are composed of opposing sets of neural clusters or “nuclei”.   These pairs of neural clusters act in an oscillating ying-and-yang fashion to achieve homeostasis. In both the hypothalamus and amygdala, the external or lateral nuclei activate the parasympathetic nervous system, associated with hunger and digestion, pleasure, relaxation and sexual arousal.  In the case of appetite, stimulation of neurons in the lateral hypothalamus (LH) increases  appetite, releases serotonin and dopamine, and activates anabolic storage of  glucose and fatty acids,  In opposition to the lateral nuclei, internal or “medial” nuclei activate the sympathetic (“fight or flight”) nervous system, which readies the organism for action, increases heart rate, suppresses appetite and sexual desire, stimulates release of acetylcholine and norepinephrine, and activates catabolic mobilization of nutrients such as fat or glycogen.  Stimulation of the medial nuclei are also associated with “aversive” non-pleasurable sensation.

Similar pairings of opposing limbic nuclei exist for neurons that control thirst, body temperature, the sleep/wake cycle, or activate social or sexual arousal.

The amygdala has a parallel structure to that of the hypothalamus, which allows direct two-way communication between them.   As Joseph notes:

Moreover, through the massive interconnections maintained with the lateral and medial (ventromedial) hypothalamus, the amygdala is able to act directly on this structure, driving the hypothalamus, so to speak, and thus tapping into its emotional reserviour so that its ends may be met. Indeed, it is able to modulate hypothalamic activity through inhibitory and excitatory projections to this structure. Direct stimulation of the basolateral amygdala and the ventral amydalofugal pathway excites the principle neurons of the medial hypothalamus. By contrast, stimulation of the medial (ventro-medial) amygdala and the stria terminalis pathway, inhibits these same hypothalamic neurons. Hence, whereas the lateral amydala exerts excitatory influences on the hypothalamus, the medial amygdala exerts inhibitory influences, and can thus control, or at least exert excitatory/inhibitory and thus modulatory influences on hunger, thirst, sexual arousal, rage, etc., as well as hormonal, endocrine, and other functions associated with the hypothalamic nuclues. Indeed, the amygdala can be likened to the chief executive of the limbic system and weilds enormous power via its control over the hypothalamus.

Similar sets of paired hypothalamic and amydaloid nuclei govern the balances that control thirst, body temperature, sleep and sex drive.  For example, osmoreceptors that monitor the concentration of salt ions in blood control thirst, and respond by adjusting the hormone vasopressin to regulate water retention by the kidney. Thermoceptors in the body and hypothalamus activate different nuclei in the hypothalamus.

Generalized versus conditioned desires. By serving as the “interpreter” that provides higher-level emotive “meaning” to raw sensory inputs, the amygdala plays a prominent role in learning and laying down reward circuitry.  In effect, it turns complex sensory inputs into cues that the hypothalamus can act upon by establishing Pavlovian circuits that automate the way your basic drives respond to the external environment and even your thoughts.  This applies to both attractive (stimulatory) and aversive (inhibitory) stimuli. As mentioned above, the reward circuitry utilizes a high concentration of dopaminergic neurons to reinforce powerful learned responses of the hypothalamus to sensory cues and thought patterns.

While the hypothalamus activates generalized drives and provides hard-wired low-level responses to universal and fairly general cues, the amygdala provides finely tuned and highly specific learned responses that can modify or override these low level cues:

The hypothalamus gets hungry and anything will do…,but the amygdala is picky about which foods it likes or dislikes, to the point of craving a specific type of chocolate with a certain texture, or rejecting a wine with a slight off-note
The hypothalamus wants sex…but the amygdala is selective about what turns it on — down to very fine preferences regarding appearance, aroma, or even sense of humor.  It may be so selective as to be monogamous!
The hypothalamus wants to sleep… but the amygdala picks up cues about danger that can rally your alertness.

The key point is this:   The generic drives of the hypothalamus are equally powerful whether they are activated by low level chemical and nerve inputs from the blood stream or stomach nerves — or rather by higher level perceptual and emotional inputs from the amygdala.  And if the reward circuitry from the amygdala is strong enough, it can override the low level signals.   A Pavlovian response to the aroma of a juicy steak or the sight of a decadent chocolate cake can activate the hunger response and fat storage program initiated in the lateral hypothalamus, regardless of the nutritional state conveyed by blood glucose or leptin and insulin levels.  Conversely, an unappetizing meal, or an emotional shock can quickly suppress appetite or activate a state of arousal and access to energy.

The hypothalamus doesn’t know or care why it is getting hungry, sleepy or sexed up.   It matters not whether the signals are based on blood chemicals or high level emotional perception — the actions taken by the hypothalamus are identical in either case.

An aside on food reward. This dual model of direct hypothalamic regulation versus conditioned amygdaloid regulation of drives like hunger can shed some light on the recent debate about the Food Reward Hypothesis of obesity.  Stephan Guyenet has cited compelling evidence for the FRH, based on the  observation that rats fed a “cafeteria diet” of highly palatable junk food became fatter than rats fed calorically matched standard bland rat chow.  Merely adding flavor or flavor variety to the chow also resulted in fatter rats.

However, in an earlier post, “Does tasty food make us fat?“,  I argued that Guyenet’s version of the FRH suffers from two logical flaws:  First, Guyenet does not take a clear position on whether “reward” is an inherent property of foods, or rather a learned or conditioned property, relative to individual and cultural experience.  Second, while rewarding food is associated with obesity, the causal sequence can be questioned.  I think it is likely food reward is the is the consequence, not the driver of psycho-metabolic dysregulation.  Food becomes rewarding only after primary hypothalamic regulation becomes impaired, for example by the way that the particular fats and sugars in junk food desensitize hypothalamic receptors to insulin or leptin, as I described in “Obesity starts in the brain“.   Of course, once the amygdaloid food reward circuits are established, they can be expected to perpetuate an increased appetite and shift away from fat mobilization to fat storage.  But the amygdaloid reward circuit is not the primary defect — that remains the impairment to the hypothalamus.  The proof is that it is not just appetite that is impaired — it is also the metabolic consequence of a more active lateral hypothalamus and inhibited ventromedial hypothalamus.   If the hypothermic defect is repaired, the food reward circuit should extinguish.

THE BOTTOM LINE

Hormesis and the hypothalamus.   So how do we use this information?  Specifically, how do we “judiciously” apply “stress”s to re-program our limbic control system. What if we are gaining weight due to both a strong appetite and more “efficient” storage. Or what if we have trouble falling and staying asleep?  Or (more speculatively) what if we want to become more or less aggressive, or more or less sexually motivated?

In short, our understanding of the limbic system suggestions two approaches:

1.  Direct reprogramming of the hypothalamus. Every drive is regulated by a balance of stimulatory and inhibitory neurons.  By the logic of hormesis, we can stimulate the growth of one set of neurons or the other by periodically  ”starving” them of their normal stimuli, allowing a compensatory up-regulation of receptor neurons.  Often this process is slow, and the compensating adaptations may take weeks or longer — but with sustainable results. This is the reverse logic illustrated in several posts.

• “Change your receptors, change your set point”  demonstrates how exposure to uncomfortable stresses such as intermittent fasting, strenuous exercise, cold showers and the like can up-regulate dopaminergic neurons and thereby counteract conditions such as obesity, addiction and depression.  While the research cited in that article doesn’t specifically locate the dopamine neurons, , we know they have a high density in the hypothalamus, amygdala and other limbic structures, and the PET scans indicate a brain location consistent with the hypothalamus and amygdala.
• “A cure for insomnia?” describes the use of Sleep Restriction Therapy (SRT).  By forcing extended wake cycles, there is an apparent rebalancing of hypothalamic neurons in the ascending arousal system, thereby activating sleep-active neurons in the ventrolateral preoptic nucleus (VLPO) associated with the  “flip-flop switch” that produces distinct sleep-wake states.  As a result, SRT reduces the  excessive production of corticotropin-releasing factor (CRF) that is associated with many cases of insomnia.

Where does obesity begin?  What drives you to eat too much or expend too little energy, and why has there been such a dramatic increase in obesity since 1980? Some recently popular explanations are the carbohydrate / insulin hypothesis (CIH), singling out the prevalence of carbohydrates in the diet, and the food reward hypothesis (FRH), putting the primary blame on the availability of “hyper-palatable” food.

In this post I will present evidence for new paradigm, which I call the  Hypothalamic Hypothesis (HH).  I think it provides a better explanation for the facts of obesity than the CIH and FRH theories, and leads to some different advice about how best to lose weight.

Some recent research suggests that obesity starts with specific physical changes to the brain. Appetite is regulated by the hypothalamus, particularly the arcuate nucleus (ARC), ventromedial hypothalamus (VMH) and lateral hypothalamus (LH). It turns out that two very specific changes to the brain cause us to get get hungry, overeat, burn less fat, and gain weight. And these changes to particular brain structures come about as a result of what you eat, eating frequency, and to some extent your activity level. The problem of obesity or overweight is often portrayed as a single problem, but it is really two problems, and each type of obesity corresponds to one type of brain alteration. Failure to distinguish these two types of obesity has resulted in much confusion. In part, the confusion comes about because these two types of obesity frequently occur together in the same individual, although one type is usually dominant. If you understand this, and you understand the role your brain plays, you can become more successful at losing excess weight.

I’ll spend a little time explaining the theory, provide some specific suggestions for how it can help you fine tune your weight loss program, and try to point out why I think the Hypothalamic Hypothesis overcomes some weaknesses of the other obesity theories.

Two types of obesity.  One major type of obesity is subcutaneous (SC) obesity.  The man on the right is a Sumo wrestler with subcutaneous obesity,  but you don’t have to be a wrestler to have this type of fat distribution.  It is characterized by lots of looser, softer fat hanging from the torso, arms, legs and even the face.  A double chin and skin folds under the arms are not uncommon for this type.  SC obesity is more common among women than men.

The second major type of obesity is visceral or “intra-abdominal” (IA) obesity. This is depicted by the classic “beer belly” sported by the main in the left photograph, characterized by a protuberant gut, but frequently not a lot of extra fat on the legs or arms. It’s quite prevalent among men, but seen on many women as well.

The above photos show extreme types, but it is common for both types of obesity to coexist in the same person, in varying degrees.  Those with predominant IA obesity are sometimes referred to as “apples”; those with predominant SC obesity are called “pears”.

Different metabolisms. The difference between subcutaneous and intra-abdominal obesity is not merely a matter of how adipose tissue is distributed on the body, but also about the biological composition of the fat tissue and it’s metabolic activity.  Subcutaneous fat is located just beneath the skin, and on the outside of the muscle tissue, all over the body.  By contrast, intra-abdominal fat– also called visceral fat–is located underneath the visceral muscles, deep within the gut.  It  surrounds the digestive organs — the liver, pancreas, stomach and intestines.  The difference can be seen clearly in the CT scans at the left.  The top image shows a cross-section at mid-belly level of someone with SC obesity, with most of the dark gray fat mass located right under the skin but outside the lighter grey visceral muscles and internal organs.  The bottom image is a similar CT scan of someone with IA obesity, showing much less subcutaneous fat, but considerable fat beneath the walls of the viscera, packed around the intestines.

What is important to realize is that the adipose tissue stored inside the abdomen is biochemically and metabolically very different than the fat stored right under the skin.  Both are called “fat” or “adipose tissue” but they behave as if they were entirely different substances. The image below at left is a micrograph of SC fat; the image at right shows IA fat cells.  Notice the different shape and size, but also the substantial dark “mortar” between the IA fat cell “bricks”.

The adipose tissue in IA fat is not an inert storage tissue.  On the contrary, it is a metabolically active hormonal “organ”: it is infiltrated by macrophages and secretes “adipokines” like interleukin-6, tumor necrosis factor alpha, and C-reactive protein.  These compounds are inflammatory signaling agents, associated with insulin resistance, diabetes, hypertension, and cardiovascular disease characteristic of Metabolic Syndrome.  The health effects of this inflammatory process have been the subject of intense study.  In this article, however, I’ll address only the role that these inflammatory processes have in the development of obesity.

The appetite center.  To understand the dynamics of each type of obesity, it is important to understand how appetite and body fat are governed by the brain. The hypothalamus regulates biological drives, including feeding, sleep and hunger.  As shown in the diagram at right (and also in this video) appetite, feeding behavior and metabolic rate are regulated by two sets of neurons that have opposite effects on appetite and metabolism:

• The  ”anorexigenic” POMC/CART neurons that inhibit appetite and increase the rate of fat oxidation in the body.  In response to nutrients and certain hormones, these neurons produce the appetite-suppressing neuropeptides propio-melanocortin, cocaine-and-amphetamine-regulated transcript and α-melanocyte stimulating hormone (α-MSH). The α-MSH binds to and activates secondary melanocortin-4 (MC-4) neurons in the ventromedial hypothalamus (VHM), causing satiety and increasing energy expenditure and  fat oxidation in the body. Animals with damaged or lesioned POMC/CART neurons eat voraciously and become obese.  Both leptin and insulin are potent hormonal stimulators of the POMC/CART neurons.  These neurons have receptors for appetite suppressing signals like insulin and leptin; low levels of either hormone will increase appetite and reduce metabolic rate. If  a deficiency of leptin or insulin persists, it will lead to obesity.
• The  ”orexigenic” NPY/AgRP neurons that stimulate appetite and slow down fat oxidation in the body.  These neurons produce two neuropeptides — neuropeptide Y (NPY) and agouti-related protein (AgRP) which act to inhibit α-MSH from binding to and activating the MC-4 satiety neurons and stimulates melanin-concentrating hormone (MCH) in the lateral hypothalamus (LH). This inhibition of MC-4 and stimulation of MCH enhances appetite and decreases metabolism and energy expenditure, conserving fat.  Animals in which the NPY/AgRP neurons have been damaged or destroyed by lesions become anorexic and lose weight.  Insulin and leptin inhibit the NPY/AgRP neurons, whereas the “meal timing” hormone ghrelin, which cyclically ebbs and flows, stimulates them.

These two sets of neurons govern fat gain and fat loss.  They effectively sense the energy status of body by centrally integrating inputs from a large number of circulating nutrients, neuropeptides and hormones, and they respond by outputting neuropeptides that drive behavior and peripheral metabolism. When they are in balance, a normal and healthful level of body fat is maintained, but when the balance of  orexigenic or anorexigenic signals shift, this adjusts the body’s fat and activity set points up or down.  As a prime example, if leptin levels in the hypothalamus are low, either because of low body weight or because the leptin is blocked from reaching its receptors in the POMC neurons, appetite will increase, fat oxidation will decrease, and this will lead to an increase in adiposity.

Insulin, leptin and appetite. There are two hormones which predominantly regulate body fat:  insulin and leptin. In healthy individuals, as Byron Richards describes,

Leptin uses adrenaline as a communication signal to fat cells, telling them to release stored fat to be used for fuel. This takes place in the course of a normal day between meals and at night during sleep…A drop in leptin signals hunger. Food intake stimulates insulin release. As a person eats, insulin is always directing some amount of triglycerides to go over to white adipose tissue and enter fat cells….This turns on the production of leptin in fat cells, causing the blood level to rise in response to the meal. As the leptin levels rise high enough, they signal to the brain that enough has been eaten. Leptin now signals the pancreas to stop making insulin…In overweight people, the communications involving insulin and leptin are inefficient. It is like making a phone call where no one answers. Insulin and leptin resistance mean that the hormones don’t communicate efficiently in response to food.” (The Leptin Diet, p. 13, 17, 23, 36)

Increased basal levels of either of these two hormones indicates increased energy stores and adiposity. The hormones have different metabolic effects depending on their site of action.  As Lustig explains, the action of these hormones “centrally” — inside the brain — is entirely different than that in the “periphery” — the rest of the body:

Insulin also plays a pivotal role in the control of appetite and feeding. In addition to its well-defined peripheral role in glucose clearance and utilization, insulin is involved in the afferent (and efferent) hypothalamic pathways governing energy intake, and in the limbic system’s control of pleasurable responses to food. Whereas insulin drives the accumulation of energy stores in liver, fat, and muscle, its role in the CNS tends to decrease energy intake. This is not a paradox, but rather an elegant instance of negative feedback. When energy stores abound, circulating insulin tends to be high; high CNS insulin tends to decrease feeding behaviors, thereby curtailing further accumulation of energy stores. Insulin’s central effects on energy intake are manifested in two complementary ways: first, insulin decreases the drive to eat; second, insulin decreases the pleasurable and motivating aspects of food.

This self-limiting regulatory action of insulin is also noted by Banks:

Insulin plays many roles within the CNS. Several laboratories have shown that some of the CNS effects of insulin are the opposite of those effects mediated through peripheral tissues. In particular, CNS insulin increases glucose and inhibits feeding, whereas serum insulin decreases glucose and increases feeding. Thus, to some extent, insulin acts as its own counterregulatory hormone, with CNS insulin producing features of insulin resistance.

Both insulin and leptin have an appetite suppressing effect when an elevated level of either one reaches the appetite center of the brain, specifically the satiety-inducing POMC/CART neurons within the arcuate nucleus (ARC) of the hypothalamus.  While similar in their appetite suppressing effect, insulin levels fluctuate in response to the ingestion of meals, especially carbohydrate-rich meals, whereas leptin levels generally reflects longer term changes in energy stores.   Most noteworthy for this discussion, however, these two hormones reflect the two different types of fat.  According to Woods et al:

Insulin is secreted in proportion to visceral fat, whereas leptin reflects total fat mass and especially subcutaneous fat. This is an important distinction with regard to the message conveyed to the brain, since visceral fat carries a greater risk factor for the metabolic complications associated with obesity than does subcutaneous fat. Elevated visceral fat carries an increased risk for insulin resistance, type 2 diabetes, hypertension, cardiovascular disease, and certain cancers. Hence, leptin and insulin each convey specific information to the brain regarding the distribution of fat, and the combination of the two additionally conveys information as to the total fat mass of the body.

Interestingly, Woods also reports the brains of females are more sensitive to leptin than insulin, whereas the reverse is true in males, and that estrogen mediates this difference.   According to  Cnop el at., women on average have three times as much leptin as men, even after controlling for comparable degrees of body mass and insulin resistance. Which explains why there are more male “apples” and more female “pears” — though of course both types of obesity are represented to varying degrees in both genders.

While the appetite regulating actions of insulin and leptin within the brain are well known, what is less well known is that these the two hormones also use “remote control” from within the brain to activate fat loss in the rest of the body.  According to Woods:

As previously mentioned, when leptin is administered into the brains of experimental animals, there is a selective reduction of body fat, with lean body mass being spared. Likewise, when insulin is administered into the brain, there is a reduction of the respiratory quotient, suggesting that the body is oxidizing relatively more fat. These observations suggest that one action of these adipose signals within the brain is to reduce body fat, and a corollary of this is that fat ingestion would be expected to be reduced as well. Consistent with this, we have observed that when insulin is administered into the third cerebral ventricle of rats, fat intake is selectively reduced. Hence, it is reasonable to hypothesize that leptin and insulin, acting in the brain, reduce body fat by increasing lipid mobilization and oxidation and simultaneously by reducing the consumption of dietary fat.

In short, if you want to control your appetite and burn fat faster,  you want leptin and insulin to get inside your brain!  The problem in obesity is that these hormones are not adequately reaching and communicating with the appetite center of the hypothalamus.

Putting up resistance.  So far, I’ve described how leptin and insulin work to homeostatically regulate appetite and body fat in normal individuals.  But this carefully balanced feedback system becomea derailed in obesity.  There are some interesting, but fortunately rare, genetic or disease conditions where the leptin or insulin sensitive receptors in the hypothalamus become defective and insensitive to leptin or insulin. In other words, the “off” switch for appetite stops working correctly.  Or where the leptin or insulin molecules themselves are mutated or damaged and are thus unable to turn off the appetite switch.  Animals or humans with these defects eat voraciously, insatiably and become extremely obese. These rare cases provided some of the initial evidence for the current understanding of how leptin and insulin regulate appetite and body weight.

But defective  hormones and receptors are rare and do not explain the vast majority of cases of obesity. The “normal” cause of obesity involves involves leptin resistance or hypothalamic insulin resistance, whereby there is plenty of leptin or insulin circulating in the bloodstream, and the appetite-suppressing POMC neurons are functional, but not all of the hormone is reaching the receptors in the hypothalamus. The messenger is yelling, but the ears hear the message faintly.  There is a barrier or impediment between messenger and receiver.   The result in each case is that appetite is not getting satisfied, so there is a drive to overeat.  And furthermore, as Woods notes, the “remote control” fat burning functions of the hypothalamus are also reduced.  As a result, with more eating and less fat mobilization and oxidation, you get fatter.

Now, let’s see in more detail what happens to the hypothalamus in each main type of obesity.

Subcutaneous (SC) obesity and the brain.  Leptin is produced in adipose tissue, but specifically in SC fat.  The more SC fat, the more elevated the leptin concentration in the blood.  Normally this would provide a negative feedback signal, inducing satiety in the hypothalamus and increasing the release of fatty acids from fat cells.  In SC obesity, however, only a low level of this leptin is reaching the hypothalamus, so appetite and eating are not inhibited.  But why does this happen?  What is the mechanism?

Some, like Lustig, see insulin resistance in the brain as a likely driver of leptin resistance:

Hyperinsulinemia itself may be a cause of leptin resistance. As described, insulin and leptin use many of the same neurons, the same second messengers, and the same distal efferents to effect induction of satiety….Although confirmation in animal studies is needed…CNS insulin resistance may be a proximate cause of leptin resistance, promoting continued weight gain.

However, it is not plausible to blame leptin resistance on insulin resistance, because many of the obese are insulin sensitive.  For example, Sumo wrestlers notably  can weigh 500 pounds or more,  but they are typically insulin sensitive, and have low cholesterol. According to an study by  Gerald Reaven of Stanford:

The ability of insulin to mediate glucose disposal varies more than six-fold in an apparently healthy population, and approximately one third of the most insulin-resistant of these individuals are at increased risk to develop cardiovascular disease. Differences in degree of adiposity account for approximately 25% of this variability, and another 25% varies as a function of level of physical fitness. The more overweight/obese the person, the more likely they are to be insulin-resistant and at increased risk of cardiovascular disease, but substantial numbers of overweight/obese individuals remain insulin-sensitive, and not all insulin-resistant persons are obese.

Recent evidence suggests that the crux of leptin resistance can be located at the door to the brain:  the blood-brain barrier (BBB).  The BBB is semipermeable along the arcuate nucleus.  This allows for controlled, selective transport of various nutrients and energy signals.  According to Banks,

The blood–brain barrier (BBB) prevents the unrestricted movement of peptides and proteins between the brain and blood. However, some peptides and regulatory proteins can cross the BBB by saturable and non-saturable mechanisms. Leptin and insulin each cross the BBB by their own transporters. Impaired transport of leptin occurs in obesity and accounts for peripheral resistance; that is, the condition wherein an obese animal loses weight when given leptin directly into the brain but not when given leptin peripherally. Leptin transport is also inhibited in starvation and by hypertriglyceridemia. Since hypertriglyceridemia occurs in both starvation and obesity, we have postulated that the peripheral resistance induced by hypertriglyceridemia may have evolved as an adaptive mechanism in response to starvation.

In a study on mice, Banks et al. showed  that triglycerides, but not free fatty acids, induce leptin resistance.  This same study showed that, that fasting for 16 hours reduced triglycerides and increased leptin transport, whereas fasting for 48 hours increased triglycerides and impaired leptin transport. This provides support for intermittent fasting as a strategy to reverse leptin resistance.  Elevated triglycerides also enhance the transport of ghrelin, the hormone responsible for initiating feeding at conditioned meal times, which explains why certain obese people get especially hungry around meal time.

Triglyceride levels tend to increase with your degree of adiposity.  But what causes them to rise in the first place?  The primary culprit seems to be fructose, which is converted to triglycerides if consumed in excess. Of course, fructose is part of sucrose and high fructose corn syrup, so any of these sugars in excess will elevate triglycerides, cause leptin resistance, and SC obesity.  Foods containing high concentrations of sugar include  sodas, candies, breakfast cereal, bread and other baked goods, but also sugary fruits like bananas, mangos and raisins. Michael Eades recognized the connection between triglycerides, the blood brain barrier and appetite in his 2007 blog post “Leptin, low-carb and hunger“. But I suspect that it is specifically the effect of fructose reduction — and not the generalized carbohydrate reduction postulated by Eades– that is the primary explanation for low carb diets work to reduce appetite so well for many people.

Diet, of course, is not the only factor affecting how the blood-brain barrier affect leptin resistance.  For example, Banks also notes that epinephrine enhances leptin transport across the BBB by a factor of 2-3 fold.  This explains why exercise and excitement can act to suppress appetite.

Intra-abdominal (IA) obesity and the brain.  Insulin is produced by the pancreas, when it circulates through most of the body outside the brain and spinal cord — what physiologists call the “periphery” — it’s main function is to regulate the availability and storage of glucose and fatty acids, thus preventing excessive glucose or fatty acid levels in the bloodstream.  When insulin receptors in liver, muscle, and other tissues become less responsive to insulin, the resulting insulin resistance results in hyperinsulinemia and its associated metabolic derangements such as Type 2 diabetes. There has been much investigation regarding what causes insulin resistance, the lead hypothesis being some sort of inflammation due to many suspects, including certain fats.

Unlike leptin, triglycerides do not impair insulin transport into the brain. According to a study by Urama and Banks,

[T]he triglyceride triolein significantly increased the brain uptake of insulin, an effect opposite to that on leptin transport, in starved obese mice….That is, leptin transport across the BBB increased with short-term fasting but decreased with starvation and with administration of triolein. In contrast, insulin transport is decreased by short-term fasting but increased by starvation and by triolein.

So what, if not triglycerides, leads to insulin resistance in the brain?

The answer appears to be: free fatty acids. Certain fatty acids – trans fats, certain long-chain saturated fatty acids, and omega-6 unsaturated fatty acids  – produce an inflammatory response in insulin receptors that blunts insulin sensitivity. By contrast, other fatty acids — principally omega-3 fatty acids (like flax or fish oil) and short or medium chain triglycerides (like coconut oil) — are actually anti-inflammatory).  Certain sugars like fructose also appear to be pro-inflammatory.  But what has not been recognized until recently is that these inflammatory processes occur not just in the liver and muscles, but also within the hypothalamus.

And in fact, inflammation of the hypothalamus may be where insulin resistance starts.

Posey et al found that mice fed a high fat diet, with equal calories to a low fat diet, gained 60% more adipose tissue than those on the low fat diet.  Other experiments by Kaivala et al. showed a high fat diet resulted in a 60% reduction in CNS insulin levels, inversely associated with changes in body weight. Thaler et al. , Schwartz et al and Benoit et al. showed that  one particular long chain saturated fatty acid — palmitic acid — causes inflammation and reduces insulin sensitivity in the hypothalamus, leading to overeating and obesity.  Arruda et al. found that intracerebroventricular  injection of an inflammatory cytokine (TNF-α) or stearic acid (another long chain saturated fatty acid) into lean rats induced insulin and leptin resistance in the hypothalamus and hyperinsulinemia and down regulated thermogenesis and oxygen utilization.  In TNF knockout rats (those missing the TNF receptor), the TNF-α did not produce any of these effects, and the rats were protected.  Furthermore, Araujo et al showed that co-administrering an anti-inflammatory drug (infliximab) restored normal oxygen consumption in the obese rats.  Similar results from other studies have been reviewed by Schwartz et al .

Interestingly, high levels of fructose can also cause inflammation and insulin resistance, leading to IA obesity.  If you are lean and healthy, fructose at reasonable levels is converted to glucose in the liver, and brief excess is then stored as glycogen in the liver and muscles.  But in vast excess, fructose is converted to fat of two types — triglycerides and one particular fatty acid.  Can you guess which fatty acid?  The answer is palmitic acid, the fatty acid associated with brain insulin resistance. The liver begins to accumulate the excess fat – a condition known as steatosis or fatty liver disease — which results in hepatic insulin resistance.   So while high fructose consumption causes elevated triglycerides, those triglycerides cause leptin resistance and are not a direct cause of insulin resistance. do not cause insulin resistance, only So it looks like fructose (and of course sucrose which is 50% fructose) is involved in the genesis of both SC obesity and IA obesity.  The fact  is just one manifestation of how easy it is to get confused about “the cause” of obesity.  Because there are two types of obesity with different but intertwined etiologies, the logic of obesity is not always so easy to sort out.  But the various diveres causal threads always come together in the arcuate nucleus of the hypothalamus

What is most illuminating, however, is research by Ono et al showing that hypothalamic insulin resistance precedes — and probably causes — insulin resistance in other organs and tissues.  Ono found that feeding rats a high fat diet induced insulin resistance in the hypothalamus after only one day, with no concurrent hepatic insulin resistance!  It took a full 3 days on this diet for insulin resistance to show up in the liver, and 7 days for the muscles and peripheral tissues to become insulin resistant.   The mechanism of inflammation was the activation of the mTOR/S6K pathway by exposure to fatty acids.  The S6K protein apparently inhibits insulin signaling in the arcuate nucleus of the hypothalamus, activating the orexigenic NPY/ArGP neurons and inhibiting the POMC neurons.  Similarly, Pagotta has marshalled other evidence suggesting that insulin resistance starts in the brain.  Of particular note is a study by Obici et al, in which central administration of insulin suppressed glucose production by the liver, and blocking insulin signaling in the brain impaired the ability of insulin to inhibit glucose production in the liver. Finally, an excellent post by Stephan Guyenet cites a similar study by Morton and Schwarz showing much the same thing.  As Guyenet notes,

Investigators showed that by inhibiting insulin signaling in the brains of mice, they could diminish insulin’s ability to suppress liver glucose production by 20%, and its ability to promote glucose uptake by muscle tissue by 59%.  In other words, the majority of insulin’s ability to cause muscle to take up glucose is mediated by its effect on the brain.  

In regard to insulin signalling,  the brain seems to be in charge of the liver.  And this plays out in the genesis of insulin resistance.

This raises an interesting question:  why would insulin resistance start in the brain, rather than the liver or the muscles?  When you think about it for a few minutes, it actually makes sense.  The hypothalamus is the ultimate arbiter of whether or not the body has adequate energy intake. It does this by homeostatically regulating energy stores and energy balancing hormones. In the case of leptin resistance, as we’ve already seen, the brain acts to restore homeostasis signaling the peripheral metabolism to “grow” more subcutaneous fat (by increasing appetite and slowing fat oxidation).  If insulin signaling in the brain is blocked or impaired, homeostasis requires the initiation of compensatory processes that will bring more insulin into the brain.  But how to do that?  Insulin is not produced in the fat cells, so growing more fat won’t directly help.  To do this, the periphery must become somehow become hyperinsulinemic, in order to overcompensate so that enough insulin gets into the hypothalamus.  And the best mechanism for this is to induce whole body insulin resistance, primarily in the liver and muscles.

But how does the insulin resistant brain orchestrate insulin resistance in the periphery?  The answer, apparently, is to grow intra-abdominal fat. As Ljung notes, hypothalamic insulin resistance disrupts the hypothalamic-pituitary -adrenal axis (HPA), leading to increased secretion of ACTH and cortisol.  These hormones in turn stimulate the growth of intra-abdominal adipocytes.  The IA fat proliferates macrophages and releases pro-inflammatory  fatty acids and “adipokines” into the bloodstream. (See “Intra-Abodominal Adipose Tissue: The Culprit?“) The portal circulation carries these to the liver where they promote steatosis (fatty liver), insulin resistance, and local inflammation. The systemic circulation further carries these fatty acids and proinflammatory molecules to skeletal muscle where they promote lipid accumulation, insulin resistance, and local inflammation.  As Ross showed,  it is IA fat, not total fat or SC fat, that is associated with whole body insulin resistance.  Insulin resistance in the body causes the pancreas to go into overdrive to supply more insulin, resulting in hyperinsulimia. As basal insulin levels increase, the hypothalamus is now getting its fix of insulin, keeping hunger in check.  Of course, the level of IA obesity and hyperinsulimeia will only be what is required to handle the degree of inflammation experienced by the arcuate nucleus in the brain.  One this inflammation is reduced or removed, and the NPY/AgRP neurons become more sensitive to insulin, the requirement for elevated basal insulin should go down, and with it the need for intra-abodominal fat.

In slogan form, here is the Hypothalamic Hypothesis of Obesity:

If the hypothalamus is deficient in leptin, it directs the body to grows more subcutaneous fat.

If it is deficient in insulin, it directs the body to grow more intra-abdominal fat.

Now for some practical advice:   How can you use the Hypothalamic Hypothesis to lose unwanted fat or better control your weight?

1.  Start by assessing your degree and type of adiposity.  Do you have a waist-to-hip ratio greater than 0.8 (women) or 1.0 (men) and carry your extra weight a belly that sticks out in front? That’s IA fat and you are a probably an  ”apple”. Or do you have a waist-to-hip ratio of less than 0.8 (for women) or 1.0 (for men) and carry most of your extra weight on your butt, your thighs, chest, and possibly also your arms and neck?  That’s SC fat and you are probably a “pear”.   Of course, you may be an “apple-pear” and carry extra fat in both locations, but it is good to know which type of fat is dominant.  If you want a much more precise assessment using specific measurements of body weight, height and other body dimensions, I recommend consulting “Assessing Your Risk”, Chapter 9 in Protein Power, by Eades and Eades.

2.  If you are primarily a “pear”, and particularly if you are significantly overweight, you are leptin-resistant.  Your primary focus should be on reducing triglycerides.  Largely, this means cutting back on carbohydrates with fructose or sucrose (which is a disaccharide of fructose attached to glucose) is readily converted to triglycerides by the liver.  And it is triglycerides that primarily induce leptin-resistant SC obesity.  So of course you want to cut out soft drinks, cookies, cakes, ice cream, candies, most fruits, and most breads (except those with no sugar, which are hard to find). But so long as you are reasonably insulin sensitive, you don’t have to cut out starches.  Potatoes and rice are probably fine if you are insulin-sensitive as long as you avoid any sugar in the same meal.  If you are an “apple-pear” and are resistant to both leptin and insulin, then you can still eat fructose-free starches like potatoes and starch, but you must not add any pro-inflammatory fats. The question of what constitutes a “pro-inflammatory fat” is a controversial one.  Some fats, such as trans fats and high levels of omega-6 fats are clearly pro-inflammatory, while omega-3 fats, mono-unsaturates like olive oil, and medium chain triglycerides like coconut oil are anti-inflammatory.  But for saturated fats, the picture is less clear and the studies are all over the place.  Probably some saturated fats are OK.  But some people have found that cutting back on cheese and nuts help them shed abdominal fat.  Milk and butter from grass fed cows may be preferable to that from grain fed cows.

What about alcohol?  Alcohol is frequently assumed to raise triglyceride levels, but observational studies show this may not necessarily not true.  Moderate alcohol may actually reduce triglyceride levels.

Finally, as the Banks’ fasting study suggests, intermittent fasting (16 hours, but not 48 hours) can reduce triglycerides and restore leptin sensitivity.

3.  If you are primarily an “apple”, pre diabetic, or trying to lose stubborn belly fat — the last 10-20 pounds,  your primary focus should be on eating a non-inflammatory diet.  For the most part, this means cutting back on certain fats — trans fats (anything “partially hydrogenated” on the nutrition label), vegetable fats high in omega-6 oils, and perhaps certain saturated fats like those in meat, milk, butter or cheese from grain-fed cows. As mentioned above, the question of which saturated fats are “pro-inflammatory” is controversial. The strongest evidence that connects saturated fatty acids to brain insulin resistance is for palmitic acid, but that does not mean all saturated fatty acids cause insulin resistance. In any case, don’t shun non-inflammatory fats like fish oil, olive oil, or coconut oil.  Adding these to your meals can help reverse IA obesity.  I’ve personally found coconut oil to be great for energy and weight loss.

Because consuming high levels of sugar in the diet (fructose, sucrose or syrups that contain them) causes output of pro-inflammatory palmitic acid,  foods containing sugar should be restricted.  If you are lean and have a have a healthy liver, I see nothing wrong with fructose in moderate quantitates.  The daily apple will not hurt you, but the excessive amounts of sugar in  sodas, pastries, ice cream, bread (which contains sugar)  sweet fruit — make you (or maintain you as)  both a  ”pear” and an”apple”.

In addition to avoiding high levels of certain fatty acids and sugars, inflammation can also be reversed by a few additional steps:

• ensuring adequate intake anti-inflammatory micronutrients such as Vitamin D and magnesium
• high intensity exercise, intermittent fasting, cold showers and other hormetic stressors which upregulate anti-inflammatory brain compounds such as BDNF

Caveats. In making the above suggestions, I would like to make a disclaimer:  This post is primarily about a new paradigm of obesity, but I realize that people are looking for specific dietary recommendations.  The  above dietary advice is based upon my best attempt to interpret two general principles regarding the effects of triglycerides and inflammation on the appetite center of the hypothalamus.  In doing this, I am relying on a large body of empirical evidence that is sometimes ambiguous or contradictory — for example, regarding which saturated fats are pro-inflammatory, and which are protective.  And so I may be wrong about the hypothalamic effect of this or that specific food.  Despite this uncertainly, the HH provides a test for deciding whether a food or practice is obesogenic and leads to overeating: namely whether it raises triglycerides or inflames the hypothalamus.  And it is also apparent that these guidelines for foods to avoid cut across conventional macronutrient categories like “fat” and “carbohydrate”, since the hypothalamus does not sort things out that way.

…

OTHER THEORIES OF OBESITY.  I would like to close by contrasting the Hypothalamic Hypothesis with two other theories of obesity, showing how it better accounts for certain facts, and leads to perhaps some different recommendations for losing excess body fat.

The Carbohydrate / Insulin Hypothesis (CIH).  Most prominently advocated by Gary Taubes, CIH holds that dietary fat plays no role in obesity.  Rather, dietary carbohydrates, through their stimulation of insulin secretion, result in a greater degree of fat storage. Carbohydrates drive insulin drives net fat storage. Obesity is a disorder of excess fat accumulation, not overeating or inadequate energy expenditure.  In its favor, CIH can account for the close correlation between obesity and hyperinsulinemia, and the success of low carb dieting.  However, it manifestly does not explain why many obese people, like Sumo wrestlers, are insulin sensitive, with normal insulin levels and no indications of diabetes, cardiovascular disease, or other signs of Metabolic Syndrome.  It also does not account for why others, such as the Kitavans and Okinawans, can  eat a diet low in fat but high in certain starchy carbohydrates (polymers of glucose) like root vegetables or rice, and remain lean, with low basal insulin levels.  And it cannot explain why, despite sincere attempts, many people can lose only a certain amount of weight (probably subcutaneous fat) on low carb diets, but often stall and remain insulin resistant when continuing to eat a high fat / low carb diet.  The HH can explain all these facts by carefully distinguishing SC obesity from IA obesity, and by narrowing the cause of type of obesity to very specific types of carbohydrate (fructose and sucrose) and fat (long chain saturates, trans fats and omega-6 fats).  And, perhaps heretically, HH predicts that once you’ve maxed out the benefits of low carb, you can get rid of that paunch and insulin resistance by cutting back on fats– at least the pro-inflammatory fats.

The CIH also cannot explain certain anomalies such that described by Stephan Guyenet and Chris Masterjohn:  the LIRKO mouse which has severe hepatic insulin resistance and hyperinsulinemia — but remains leaner than its normal counterparts.  Guyenet and Masterjohn seem to conclude from this that insulin resistance cannot be a cause of obesity.  The mistake they make, I believe, is overlooking the possibility that only one type of insulin resistance — that of the hypothalamus — leads to obesity.  The LIRKO mouse they discuss had an insulin resistant liver, but apparently a well functioning hypothalamus.  It would have been interesting to feed it some pro-inflammatory fats to see what would happen.

One further aside about the CIH:  I must admit that I was previously persuaded by the orthodox version of CIH and it’s explanation about hunger–which I now suspect is incorrect.  I employed this theory elsewhere in this blog to explain the appetite-suppressing effect of low carb diets, intermittent fasting, and flavor control diets such as the Shangri-La Diet.  The explanation was based on what I thought was a very plausible theory I first encountered in Gary Taubes’ Good Calories, Bad Calories, Chapter 24,”Hunger and Satiety.” .  The insulin-lowering effect of low carb diets is supposed to counteract hunger from hypoglycemia by making glucose and free fatty acids more available.  And the appetite inducing effects of  appetitive flavors or aromas is explained by their action (probably via the vagus nerve, mediated by the brain’s  tractus solitarus) in eliciting a preprandial insulin response.  This preprandial insulin response supposedly causes a sudden drop in  blood glucose, inducing hunger.   I now believe this theory is wrong, or at least incomplete, for several reasons.  Primary among those reasons are my own experience with blood glucose self monitoring, where I noticed that my blood glucose would typically drop after, but not before I would get hungry.  Also, preprandial insulin responses are typically fairly small and unlikely to reduce blood sugar enough to induce hypoglycemic hunger. So the preprandial insulin response seems too little, too late.  It is more likely an effect, not a cause, of hunger.  I now suspect that a more likely explanation would be the direct action of the vagus nerve and tractus solitarus on the orexigenic or anorexigenic neurons in the ARC, or on the permeability of the blood brain barrier.  But that will be a topic for another post.

The Food Reward Hypothesis (FRH).  The most effective advocate for the FRH is Stephan Guyenet, of Whole Health Source.  Guyenet is the first to admit he is not the originator of this theory, which is common among obesity researchers and was prominently featured in David Kessler’s book, The End of Overeating. And Stephan also takes a modest stance in stipulating that he takes “food reward” to a be a major explanatory factor, but not the sole causal factor, for obesity. For example, he mentions exercise, leptin resistance, energy excess and, yes, even hypothalamic inflammation, as “other” contributory causes to obesity. So FRH is not supposed to be a monocausal theory of obesity. But modesty aside, Guyenet has put a stake in the ground and marshaled considerable argument and evidence in support of FRH.  Briefly, FRH holds that feeding people (or animals) foods have a high “reward” level results in overeating and obesity.  Here is how Guyenet defines “food reward”:

I use the term food reward to refer specifically to the motivational value of food, i.e. its ability to reinforce behavior.  For example, acquiring a taste that causes a person to seek out the food in question more often.  This is how some, but not all, researchers define the term.  Others use the term “food reward” to refer to both the motivational and the palatability value of food.  Palatability refers specifically to the enjoyment derived from a food, also called its hedonic value.  Palatability and reward typically travel together, but not always. (“The Case for Food Reward,” Oct, 1, 2011)

The theory is supported by experimental evidence, for example by the rapid weight gain seen with rats switched from ordinary chow to a  high fat, high sugar “cafeteria diet”, and further developed by referring to the effects of such diets on brain opioids, dopamine circuits and other neurochemistry. Guyenet goes on to propose a remedy for the abundance of super palatable food:  just say no.  By avoiding overly rewarding food, our brains can return to sane eating and obesity can be avoided or reversed.

I feel a certain affinity for the FRH theory because, like HH, it is a “brain-centric” theory of obesity.  Guyenet’s self-described field of research is “neurobiology of body fat regulation and obesity”, which I agree is the most promising way to study of obesity.  I’ve been excited to follow his cogent summaries of the most interesting research in this field. However, the FRH seems to have incorrectly formulated the connection between the brain and obesity.  In fact, I’ve already discussed the FRH theory in another post, “Does tasty food make us fat?“.   Here is what I wrote there:

But I think the theory is wrong, for the simple reason that it too blindly takes correlation for causation. And in doing so, it gets the causal direction mostly wrong. We don’t get fat because food has become too tasty. Rather, to a large extent, it is the metabolism and dietary habits of the obese that make food taste too good to resist, leading to insatiable appetites. And the good news is that we are not consigned to blandness.  If we eat and exercise sensibly, we can eat flavorful, delicious foods and enjoy life, without packing on the pounds.

I had not formulated the HH theory when I wrote that post, but it fits the bill of what I said there: it is the metabolic effects of the pertinent foods in “cafeteria” diets that make them “rewarding” and engender the secondary effects on pleasure-related neurotransmitters like beta endorphin, dopamine or serotonin.  What HH does is to more specifically locate the primary metabolic effects within the arcuate nucleus of the hypothalamus, rather than elsewhere in the body.

I think that HH can explain a number of things that FRH cannot.  FRH is a somewhat vague in that it does not go very far to identify what specific attributes of food make them rewarding and what specific mechanism are involved.  Somehow, sugar, fat and salt are involved. It is more like a schema than a full theory, which makes it hard to test or criticize. By contrast, HH is very specific about the mechanisms by which specific food chemistries interact with specific parts of the brain.  HH,  unlike FRH, provides an explanation for why certain “rewarding” foods will eventually lead to  either subcutaneous obesity or rather intra-abdominal obesity.   HH holds that if you are neither leptin resistant or insulin resistant, then no foods will be inherently hyper-rewarding, at least initially.  Foods only become hyper-rewarding once insulin or leptin resistance begins to manifest itself.   HH makes the further prediction that very tasty, palatable foods that contain no fructose or sucrose (or other agents that elevate triglycerides) or pro-inflammatory fats, will not lead to obesity, no matter how good they taste.

A wider perspective: The homeostatic pleasure principle.  Finally, I think that the Hypothalamic Hypothesis provides a way to connect the hormonal regulation of obesity to something overlooked by both CIH and FRH:  the role of emotion and cognition in obesity, and the relation of obesity to our wider sense of well being.  Obesity is often a response to emotional factors like stress and depression, and conversely might be reversed by cognitive techniques such as cognitive reframing and meditation.  By locating the original of obesity within the hypothalamus, it becomes plausible to understand how stress hormones like cortisol and or calming neurotransmitters like serotonin can have a powerful and direct effect on the behavior of hypothalamic neurons and their sensitivity to leptin and insulin, since these neurochemicals are lurking nearby within the “neighborhood” of the brain.  Looked at more broadly, the hypothalamus can be thought of as a homeostatic regulation system that attempts to maintain an internal subjective sense of well-being or pleasure with respect to a broad range of drives, including not just eating, but sleep, sex, aggression, fear and other emotions.   This  homeostatic “pleasure principle” is fundamental — its provides a way to translate objective needs of the organism into conscious desires and emotions.  This fits into a related line of thinking about brain receptor sensitivity that I wrote about in my post “Change your receptors, change your set point“.  Whenever there is a dysregulation of the pleasure principle, such as occurs in the appetite drive of obesity, but also in conditions such as depression or addiction, we should look within the control system itself to find out what is going wrong. And that is what the HH does, by looking for specific brain mechanisms that explain not only our subjective experience, but the way the rest of the body responds objectively in homeostatic response to physiological disturbances.

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