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 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 greates 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.

But one can come away from the study of hormesis with the misleading impression that it’s all about adjusting the level and timing of stressors to induce an appropriate adaptive or defensive response.  In this article, I would like to focus on a frequently overlooked ingredient in hormesis:  the role of intention, attitude and voluntary choice.  If you omit this ingredient, you are leaving out an important element of the way that stress helps you become stronger.

Voluntary, deliberate exposure to stress can be particularly effective in providing psychological benefits, including overcoming anxieties, obsessions and phobias, and vanquishing appetite cravings, addictions. Beyond overcoming such self-defeating tendencies, deliberate exposure works to unleash confidence and generate a sense of joy and accomplishment.

Hans Selye

General Adaptation Syndrome. Our modern understanding of stress can be traced in large part to Hans Selye, the Hungarian-born endocrinologist whose detailed studies of animals and humans under stress led to a model of stress as a generalizable force capable of causing disease.  Selye distinguished between good  stress, which he called “eustress”, and bad stress, which he called “distress”.  While acknowledging that some stress is good because it is energizing and activates our defenses, Selye spent most of his career studying the negative effects of exposure to stress, which he fit into a pattern called GAS or General Adaptation Syndrome.  Selye claimed that GAS proceeds through three stages:

• Stage 1: Alarm reaction is what is often called “flight or fight” syndrome — a quickening of the heartbeat, tensing of the muscles, release of adrenaline and a cascade of other neurochemicals.  This is typically a short term galvanizing response, reversible once the source of stress is removed.
• Stage 2: Resistance or adaptation occurs when the stressor is sustained.  Glucocorticoid hormones and catecholamines are ramped up to maintain alertness and provide a continued supply of blood glucose, and blood pressure increases to sustain tonicity of the muscles and other organs.  Positive coping and adaptation during this stage can increase resistance and immunity, although not indefinitely. With time, and if continued unimpeded without periods or rest and relaxation, this stage leads to mental fatigue, overtaxing of the adrenal glands and immune system, and vulnerability to disease
• Stage 3: Exhaustion, in which the organism becomes depleted of energy energy reserves and immunity. Mentally, it leads to emotional withdrawal and depression.  If sustained, this third stage leads to grave illness and eventual death.

While Selye did acknowledge some positive aspects of stress during Stage 1 and the Stage 2, he did not leave much room in his model to account for the beneficial biological aspects of stress. Looked at this way, only relatively mild and short-term stresses can be considered useful and positive, insofar as they activate readiness and resistance.  But even here, Selye held that repetition of Stage 1 and Stage 2 stresses can weaken and degrade resilience.  He saw chronic, repetitive, and sustained stress as uniformly damaging to both the psyche and the body. The possibility that routine or frequent stress could significantly and sustainably build resilience was something he did not address.

Learned helplessness. Angela Patmore, in her illuminating book, The Truth About Stress, points out that Selye’s model has led to an emphasis on “stress management”, which is largely about stress prevention and strategies for coping and relaxation.  While acknowledging Selye’s contributions, Patmore believes that he overlooked a key factor which can make a very big difference in whether stress is beneficial or detrimental:

In animal experiments using inescapable threat (prolonged and repeated tail shock, forced swim, water restraint, hot plate contact and other ordeals dreamed up by researchers), long-term inability to respond to perceived danger results in a syndrome that is the biological opposite of the galvanizing stress response. In this quite different response, which has nothing at all to do with survival, the subject gives up the struggle for its life and resigns itself to its fate. This is the so-called ‘third phase’ of Selye’s GAS, but it is important to realize, as Selye evidently did not, that the animal may do this in return for a degree of neural tranquilization, and that its brain may now release pentapeptides and other opiate-like substances to dull the pain and horror of its situation. The resigned animal then succumbs to morbid physiological changes…Giving up may buffer you from reality, but at considerable cost. Resignation causes the suppression or shutting down of the immune system.  If you’ve given up, why would you need an immune system anyway? (TTAS, pp. 110-111)

The act of “giving up” or resignation literally turns a switch and redirects the entire physiology of the animal’s response into a downward spiral of depression and failing health.  This is seen not only with animals, but also in human studies.  Patmore describes experiments by Martin Seligman that demonstrate much the same phenomenon:

…Seligman and his colleagues turned their attention to students, shutting them in a room with loud unpleasant noise, and various knobs that might or might not control the volume. Some continued to alter the sound levels. Others gave up. By now Seligman had developed a model of depression based on his experimental work. His concept of learned helplessness — resigned failure to act in the face of threat — has become of fulcrum of psychological research. (TTAS, p. 113)

The concept of learned helpless highlights the importance of looking beyond the type and extent of stress alone, to consider the internal mental state of the subject.  The essential factor is the perception of control and self-determination:

A number of key studies in the stress literature have highlighted the importance of control in the vulnerability to illness from distressing experiences. Here we plainly see why this is so. Those who act to help themselves assume control. Those who fail to act requlinquish it…Viktor Frankl studied [first hand] the behavior and susceptibilities of the victims of Auschwitz and Dachau, and formulated a theory of survival that he called the ‘will to meaning’. Of immense significance was self-determination. As Frankl observes: ‘Everything can be take from a man but one thing: the last of the human freedoms – to choose one’s own way.’  Taking action based on personal choice..may also send vital messages from the brain to the body to keep fighting and not fall sick. (TTAS p. 116)

Countering Selye’s GAS theory, Patmore puts forward an alternative theory of stress:

The distress-disease link that he formulated was not the direct, simple bond that he envisaged, but a complex sequence of events dependent on each individual’s psychological make-up, courage and coping skills. According to this alternative theory, disease strikes not a direct result of the response to threat, but as a result of resignation, helplessness and failure to act.  (TTAS, p. 118)

Learned control and mastery. We can take these learnings about the negative effects of learned helplessness and turn them around:  Perhaps we can enhance the effectiveness of adaptation and resistance to stress by enhancing our sense of intentionality or deliberate control when we are exposed to stress.    One way to do this is to train ourselves to become more resilient to stress by deliberately exposing ourselves.  This is well recognized in the case weight lifting or athletic training to become physically stronger and more skilled.  But I’m talking here about something more fundamental: our attitude towards facing life’s challenges and hardships.

In contrast to the modern ideology of stress management, which teaches us to avoid stress in order to stay healthy and sane, Patmore recalls that

…there was a far different school of thought, dating back to the Romans, based not on avoiding negative emotions such as fear and tension, but on rehearsing them.  Children were taught resourcefulness and mental strength by ‘character-forming pursuits’ that developed fortitude and self-mastery. By using the opposite of stress management – emotional rehearsal…our ancestors made themselves psychologically more robust….Childhood dares, games and contests, sport and adventure activities — all provide emotionally challenging experiences that help people to understand and season their own sensations and feelings, and take them through unpleasant emotions in order to achieve a resolution…

This attitude goes back at least to the Stoic philosophers such as Epictetus, Seneca and Marcus Aurelius. William Irvine, in his excellent modern reinterpretation of Stoicism, A Guide to the Good Life, notes:

Indeed, by practicing Stoic self-denial techniques over a long period, Stoics can transform themselves into individuals remarkable for their courage and self-control. They will be able to do things that others dread doing, and they will be able to refrain from things that others cannot resist doing. They will, as a result, be thoroughly in control of themselves.

By rehearsing or training techniques such as these, you can substantially improve your resilience in handling everyday stressors, whether they be physical or social and emotional.   But what about situations in which we actually have no real control, or where the outcome is highly uncertain?  Perhaps ironically, I think that fostering a sense of control can be helpful even when we may not or do not actually have much control over the situation.  By “making the involuntary voluntary”, we can transform the way the way we respond to stress at the deepest levels of both our biology and our psyche.

I think this attitude of voluntarily embracing unavoidable stress is most articulately expressed by Epictetus, the Greek Stoic and slave whose teachings have inspired two millennia of philosophical and religious thought.  Epictetus distinguished between externals — the events and actions of others which we cannot control — and internals — our values and attitudes.  A slave for much of his life, Epictetus realized how much freedom he nevertheless retained in choosing how to react to his fate. A Stoic “sage”, he said,  never finds life intolerable, but sees in every challenge as an opportunity to test and improve oneself:

You should look to the faculties that you have, and say as you behold them, ‘Bring on me now, O Zeus, whatever difficulties you will, for I have the means and the resources granted to me by yourself to bring honour to myself through whatever may come to pass.’ (TD, Book One, Ch. 6, p. 18).

Furthermore, it is by how we handle the challenges in life that our character is revealed and built:

Difficulties are the things that show what men are. Henceforth, when some difficulty befalls you, remember that god, like a wrestling-master, has matched you with a rough young man.  (TD, Book One, Ch. 24, p. 53).

By deciding to accept the hardships that come your way, as if you had deliberately chosen them, your reactions are transformed.  What may otherwise have been a stress that leads to resignation, giving up, and Selye’s third phase of exhaustion, now becomes a challenge deliberately embraced.  This does not mean deceiving oneself and pretending that you can control the uncontrollable.  Rather, it means embracing the challenge as an opportunity to demonstrate your ability to handle a physically or emotionally difficult situation with courage and grace, to grow from it, and to actually become stronger, not weaker.  Whether or not the stressor eventually diminishes or resolves, with or without your intervention, you are left more resilient as a result.

For a more detailed discussion of Stoicism and its similarity to Hormetism, the philosophy advocated in this blog, I would encourage you to read my page on Stoicism.

Real world applications.   Many of you who have read this far may be wondering: “Interesting philosophy, but how do I actually apply this to my life?”.   I’d like to answer that by illustrating with three very different examples.  Cold showers, intermittent fasting, and exposure therapy for anxiety and phobias.

Cold showers.  The single most popular page on this blog is the March 2010 article on Cold Showers. Initially, it surprised me that so many people would show an interest in something that is without any question uncomfortable. And for some people: terrifying. The article recites a number of health benefits that have been shown or claimed to result from taking cold showers or baths.  

But the article goes beyond the objective physical health benefits to describe my subjective experience of taking cold showers.  In particular, I noted that cold showers are initially quite uncomfortable, provoking an involuntary reactions like rapid breathing, a pumping heart and even laughing. While the shock and discomfort becomes less the more cold showers you take, my experience is that–unless the weather outside is hot–there is almost always hesitation and discomfort when first stepping into the cold shower. It takes an act of will to force myself to do this.  But I do it willingly because I’ve come to understand the benefits that result.  Beyond that initial hesitation upon jumping into the cold shower each morning, I embrace it and enjoy it.

The intentional, voluntary attitude makes a big difference to the experience.  Consider the case of those who must take cold showers unwillingly, perhaps because they have no hot water for a period of their lives, or perhaps were forced to take cold showers at camp or school dormitories.  I get comments from such people, and their attitude towards cold showers is typically very negative.  It is likely that they did not receive much physical or psychological benefit from taking cold showers.  Perhaps the experience even had an adverse effect on them, at least psychologically.

Intermittent fasting.  Going without food some days, or eating only one meal per day is the involuntary fate of millions of people living in poverty or near-poverty.  It can also happen to you if you become lost, stranded or trapped in a place without ready access to food.  This experience of hunger can be quite uncomfortable, even painful.

It’s entirely different matter, however, to abstain from eating periodically for 12-24 hours as a deliberate, voluntary practice.  I’m not talking about eating disorders hear, but rather the practice of intermittent fasting (IF), undertaken to achieve not merely for healthful weight management, but for the well-documented health and longevity benefits, which I’ve discussed in my video article, Intermittent fasting for health and longevity.   When you engage in IF voluntarily, you’ll surely experience moments and periods of hunger cravings.  But in just knowing that hunger cravings are expected and are possible to
“ride out” without adverse effects, you gain a sense of control over your urges. You soon come to recognize the difference between a conditioned craving that can be extinguished by training, and true biological hunger that deserves attention.  The sense of achievement in mastering your appetite, rather than being its slave, can be empowering.  

I’ve found that intermittent fasting works best for me when I am the one who controls the eating schedule. Rather than follow someone  else’s rigidly prescribed diet or eating schedule, I like the flexibility that IF affords.  I can choose which days to fast and which meals to skip, adapting the schedule to the demands of my week.  But once I make a decision, for example to skip breakfast and lunch tomorrow, I am very disciplined about sticking to my plan.  Here again, I believe that feeling “in control” plays an important role in the outcome. A prisoner forced to follow a fasting regimen against his would be much less likely to reap the benefits — unless perhaps he decided to “own” the imposed diet in the manner of Epictetus.

Exposure therapy for anxiety, obsessions, and phobias.  One of the most common and successful approaches to treating anxiety, fear and obsessive-compulsive disorder (OCD) is the use of exposure therapy.   Often this involves both a cognitive and a behavioral component, in which a therapist works with the patient to identify beliefs, emotions and responses relating to stimuli that provoke anxiety, fear, obsessive thoughts and compulsive behaviors.  Cognitive Behavioral Therapy (CBT) emphasizes the cognitive component and proceeds by demonstrating that the underlying beliefs are false or irrational.

My personal view is that the changing the behavioral component by controlled exposure to the problematic stimulus is the most important aspect of exposure therapy, and may be sufficient even without examining your beliefs. The essential element of treatment is progressive exposure to stronger stimuli until habituation or extinction occurs.  The theory of Pavlovian extinction and deconditioning is discussed in more detail on the Psychology page of this blog.

So if you have a fear of height, snakes, or social situations, you should progressively–and very gradually–expose yourself to tougher situations.  To counteract acrophobia, you could start by ascending very small elevations.  Walk to a height that just begins to make you anxious and hold there for a while, but retreat before it becomes too uncomfortable. If you fear snakes, start by looking at photographs of snakes, then handle fake rubber snakes, or observe real snakes cages at zoos.  Eventually, work on handling real, but harmless snakes for increasing amounts of time  For social situations, start with small groups of friends, and build from there.  A related version of this exposure therapy, called exposure and response prevention, has been found useful in treating OCD.  The key is to recognize the obsessive thoughts or compulsive behaviors as “escape responses” or “safety behaviors” in response to stressful stimuli, while learning to prevent the escape response to progressively stronger stimuli.

It is especially important with exposure therapies that you stay in control of the situation at all times.  There must always be an “exit hatch” that allows you to back down and escape or stop the stressful stimulus before real panic sets in.  Being forced by a therapist or third party to go beyond the edge of your comfort zone can be extremely counterproductive and anxiety-inducing.  The therapist, if any, should be at best a “guide” or coach.  If you are strongly motivated to succeed, exposure therapy may be quite effective if you do it yourself, without a therapist.

Psychology and hormesis. What all the above practices and treatments have in common is an important psychological dimension. In each situation, the extent to which the exposure process is voluntary is the key to successful hormesis.  When stress exposure is voluntary, the gains in resilience can be substantial, even when the stress faced is sustained or repeated over the long term.  Contrary to Selye, chronic and repeated exposure to stress does not invariably lead to impaired health and depression.  What is perceived as stress can be turned into an energizing stimulus, when it is approached with a willing and inviting attitude.  Just as you can decide to “give up” in the face of stress, you can make the opposite choice: to persevere and embrace mastering what challenges you.

Voluntariness is not an essential component of all types of hormesis.  For example, it is likely that low level exposures to radiation, chemical toxins and allergens build biological resilience by activating DNA and mitochondrial repair mechanisms, endogenous antioxidant enzymes, and immune responses that involve no psychological or neurological mediation.  But a surprisingly large realm of human biology, including digestive, metabolic, immune processes — has a significant psychological or neurological dimension.  An entire field — psychoneuroimmunology — has been laboring to elucidate the mechanisms of such neurologically-mediated processes.  Human intentionality — or what is sometimes called “will”– must be considered a key factor in the successful application of hormesis to improve your health.

At points, paradoxically in spite of his focus on the detrimental aspects of stress, Selye himself came close to appreciating the importance of  this.  I was particularly struck by one statement attributed to Han Selye, that succinctly crystallizes the essential insight of this entire article:

“Adopting the right attitude can convert a negative stress into a positive one.”

Many of the questions I get on this website and the forums are of this type.  People understand the general concept of hormesis, namely that exposure to controlled amounts of stress can be beneficial, because it elicits beneficial adaptive responses in the organism.  They understand that weight lifting builds muscles, and that intermittent fasting and calorie reduction can be healthful. But too much of any stressor — weight lifting, caloric restriction, sunlight, allergens  – can have adverse consequences.  With hormesis, it seems, the Goldilocks principle applies: to get a benefit, the level of stress must be “just right”.  And because it’s so easy to veer into overload, many people seek to avoid even mild stress:  Avoid allergens. Cover up with sunscreen. Eat frequent small meals. Don’t exert yourself. But if you choose this path, you forgo the possible hormetic benefits.

So how do you determine the optimum level and frequency of exposure to a stress?  And how much rest or recovery between exposures is optimal?

These are important questions, difficult to answer with certainty.  Of course, all over the Internet you will find those who tell you exactly how many days each week is optimal for lifting weights, how much sun tanning is safe or dangerous, what level of dietary carbohydrate or food restriction is optimal or unhealthy.  In some cases, they will cite studies to support their position. But there is one big problem with all this advice, even the advice based upon careful scientific studies:

Individual responses to hormetic stressors can vary significantly.

Just as responses differ between individuals, a given individual’s ability to tolerate and benefit from hormesis changes over time, and as a function of previous exposures to stressors.  This makes it virtually impossible to reduce hormesis to a simple formula. And yet, the situation may not be so hopeless.  There are actually some tools and metrics we can use to quantifiably determine whether hormesis is helping or hurting us, and thus to “adjust” the dose.

Allostasis. There is a general biological principle that can help us dial in the right level of hormesis.  The principle is called “allostasis”.  Most people are familiar with the related concept of homeostasis, the tendency of a system to maintain a constant internal state, such as the pH, temperature, or oxygen concentration of the blood, within a fairly narrow range.  This concept was developed by the famous nineteenth century biologist, Claude Bernard, who observed that organisms strive to control their internal environment, or milieu interieur, within tight physiological constraints, through physiological processes that resist disturbances from the external environment and quickly restore normal operating conditions.   This notion was later formalized by Walter Canon as “homeostasis”, the tendency of a biological system to regulate its internal environment within a stable range.

While the concept of homeostasis has some validity, in actuality it is of fairly limited application.  In fact, most biological systems do not self-regulate physiological variables within a narrow range, but tolerate a fairly wide range of variation.  During the course of a typical day, blood glucose and insulin levels rise and fall by as much as 50% or more.  Blood pressure, heart rate, and adrenaline surge upon waking and standing in the morning, and increase to further heights when engaging in vigorous exercise, or responding to threatening or emotional situations.

Bernard and Cannon developed the concept of homeostasis to apply only to regulation of the internal environment, particularly that of the cell or circulatory system. It was not intended to describe the external condition of organs or whole organisms.  Yet others have extrapolated this concept and applied it to the misleading notion of “set points”.  For example, some have advanced the idea that each of us is born with a body weight set point from which we can only deviate transiently and in a futile manner through diet and exercise, but which we are doomed to return to.  But body weight or body fat is not an “internally” regulated physiological variable, despite the efforts of some to tie this to the hormone leptin.  Rather, it is the result of a number of interacting systems, which frequently lead to a relatively stable output.  I’ve provided a more detailed critique of the set point concept in my post, Change your receptors, change your set point.

On the contrary, when you consider the whole organism, you are struck more by its variability over time than by its constancy.  Sterling, Eyer and McEwen have contrasted the stability of homeostasis with what they call “allostasis” or “stability through change”. “Stability” here does not mean a static state, but rather a dynamic physiological process which allows the organism to sustain itself in the face of external challenges.  For example, hormones like cortisol, adrenalin and catecholamines, and mediators like cytokines, allow us to adapt to changes in activity level. Digestive hormones like insulin and glucagon, and secreted digestive enzymes like proteases, amylases and lipases, allow us to effectively respond to the sudden ingestion of food, otherwise known as “meals”.  On longer time scales, major morphological changes in the overall shape and and size of the body allow animals to handle episodic changes like pregnancy, migration, or hibernation.  While organisms and physiology are stable enough to survive, they do not maintain or even strive for a state of constancy.

Allostasis, not homeostatsis, better describes how we deal with changing circumstances.

Changes which are beneficial in the short term to handle an external stress, may be harmful or pathological if maintained chronically.  So for example, glucocorticoid and catecholamine hormones such as cortisol and adrenaline are helpful, even essential, for gearing the body up to handle acute stress.  Without such hormones would we be unable to get up in the morning, much less deal with emergencies. But these same hormones become harmful or deadly when chronically elevated, causing significant damage to the cardiovascular system and neurodegenerative conditions such as depression and memory loss.  The “biphasic” effect of cortisol and other arousal hormones and catecholamines is encapsulated by the Yerkes-Dodson Law, illustrated in the figure at the right, which holds that performance increases with physiological or mental arousal, but only up to a point. When levels of arousal become too high, performance decreases.

Similarly, insulin, which is essential for the short term digestion of carbohydrates and protein, and for facilitating tissue growth, can likewise be harmful if elevated chronically, leading to obesity, cardiovascular disease, inflammatory diseases, and possibly cancer.  McEwen refers to the elevation of these stress related hormones and effectors as “allostatic load” and their chronic elevation as “allostatic overload”.

Hormones are neither good nor bad in and of themselves.  They are helpful at the right time and for the right length of time.

Alternating states and opponent processes.  I’ve written about opponent processes as an explanation for psychological adaption in my post on The opponent-process theory of emotion.  Here I would like to go further and generalize the opponent process theory to more broadly characterize our adaptive physiology.

Our natural allostatic variability typically manifests itself in an oscillation between two states or “extremes” which alternate or fluctuate over some characteristic interval of time that can range from seconds, to hours, days, months, or years.   These two states are often thought of as “high” and “low” levels of some variable hormone, enzyme or effector. But I think they are better considered merely as opposing conditions.  That’s because what appears to be “states” are really the results of underlying processes that move the organism in opposite directions — opponent processes. These processes typically come in pairs and act to balance each other, like yin and yang. It is important not to confuse the states and the opponent processes.  These alternating states are the resultant outcomes of the opponent processes; the visible “state” reflects the dominant process, but both processes are always in play to greater or lesser extents.

This concept of may be confusing, so here are a few examples of alternating states and associated opponent processes, with widely varying temporal scales. In each case “State A” exists when “Process a” dominates over “Process b”, and “State B” exists when process b dominates:

State A     State B            Process a        Process b                     Frequency

Eating      Fasting             Anabolism       Catabolism                    3-24 hrs
Waking    Sleeping           “C” process      ”S” process                   24 hrs
Exercise   Rest                Sympathetic     Parasympathetic            varies

Eating and fasting. You could attempt to characterize the A and B states as “active vs. passive”, “stressful vs. restful” or “bad vs. good” but that is not quite right. Take eating and fasting, for example.  You might argue that eating is the active or stressful state, because it places a demand on the digestive system, and the fasting period between meals allows the digestive system to recover.  However, if the fast is continued beyond a certain point, it becomes the stressor.  After about 12 hours, the stress of fasting causes a rise in catabolic “breakdown” processes, upregulates the neuroprotective hormone BDNF, and the process of autophagy activates the breakdown of intracellular materials to fuel the mitochondria. Utilized in moderation, the “stress” of fasting thereby activates beneficial processes that protect and defend us.  Once you resume eating, the “stress” of fasting is relieved and the anabolic “building” process kick in with the rise of insulin.  This has its own benefits, in repair and growth.  It is important to note that the anabolic hormones like insulin and the catabolic ones like glucagon or adrenaline are always present at some level; they never “go to zero”.  Yet one or the other is dominant at a given time, depending on the state of digestion.

Wake and sleep. Similarly, you could say that wakefulness is active and stressful, whereas sleep is passive and restorative.  But again, this would be misleading. Wakefulness and sleep are the outcome of a dynamic, alternating balance between two essential processes, the “C process” and the “S process”. The “C process” generates a wakeful state based upon activation of  the ascending arousal system, including cholinergic, noradrenergic, serotoninergic, dopaminergic, and histaminergic neurons located in the hypothalamus and other brain nuclei.  These neurons release corticotropin-releasing factor (CRF),  ACTH, and cortiosol on a regular diurnal cycle. This arousal system interacts with inhibitory “sleep-active” neurons in the ventrolateral preoptic nucleus (VLPO), releasing GABA and other sleep-inducing neurotransmitters.   These sleep promoting neutrons and neurotransmitters represent the “S” process. The result is a “flip-flop switch”  producing distinct sleep and wake states with abrupt transitions.  The “C” and “S” processes each never actually stop, but they continuously wax and wane, with one of the two becoming dominant and leading to either wakefulness and sleep. Even within the states of wakefulness and sleep there are many regular oscillating subcycles; for example REM sleep, deep sleep and light sleep. Disruptions in this process can lead to insomnia, and can be corrected by Sleep Restriction Therapy, as I’ve described in my post A cure for insomnia.

The reality is that for each basic physiological process we need both A and B states and the underlying a and b processes.  The opponent processes represent polarities of an indivisible “yin-yang” pair.  They balance each other, but not in a constant ratio.  The a and b processes cannot be indefinitely sustained, but each have within themselves the seeds of their own demise, by inducing their complementary, inhibitory process.  Biological organisms are constructed out of complementary and opposing physiological process, which naturally give rise to  an alternation between the A and B states.  This is a phenomenon I will refer to as stress oscillation.

Stress oscillation builds dynamic range.  So what does allostatis and the opponent processes have to do with hormesis?  Sometimes hormesis is thought of unidimensionally:  lift weights to build muscle.  Fast or reduce carbohydrates to lower insulin and reduce weight.

But in reality, hormesis should be thought of as a binary process of alternating stress and recovery.

Lifting weight builds muscles because it induces “catabolic” microtrauma to the muscles; it is the rest between workouts, in combination with adequate diet, that leads to the “anabolic” rebuilding of the muscle.  Both stress and recovery are necessary.  For the same reasons, weight loss through insulin lowering should be balanced with sufficient periodic insulin raising to maintain lean body mass, and maintain the healthy function of the insulin producing system, including the pancreatic secretory islets and the insulin receptors in the brain and muscle tissues.  One risk of an unremitting “insulin sparing” diet, such as a very low carbohydrate diet without periodic insulinogenesis is the induction of a state of physiological insulin resistance. This is indeed a paradoxical outcome of a diet which many pursue in order to improve their insulin sensitivity!

In the wake-sleep cycle, the ascending arousal system or “C-process” is stimulated by the secretion of CRF (corticopin releasing factor) by the hypothalamic-pituitary-adrenal (HPA) axis.  But a state of interminable wakefulness or insomnia results in cognitive deterioration. Both the “C” and “S” processes are necessary, and they must oscillate:  An unvarying simultaneous activation of both processes would not lead to cognitive stability, but rather mental deterioration.  Stress and renewal must follow one another as night follows day.

For any physiological function like digestion, muscle synthesis, or the wake-sleep cycle, the oscillation between State A and State B produces a dynamic stability that exhibits a certain dynamic range between stress and rest.   The cycle of eat-fast-eat leads to a cycling of digestive hormones such as insulin, glucagon, and adrenaline.  The cycle of wake-sleep-fast leads to a cycling between the arousal system and the sleep system.

And here is the takeway:  By exposing ourselves to alternating A and B states of increasing intensity, we build tolerance and dynamic range for the opponent processes.  We should strive to increase the magnitude of contrast between the opponent states.  I believe that we can generalize the use of dynamic capacity between allostatic states as a marker of fitness.  This can be illustrated by several examples:

Example 1.  Aerobic capacity.  Exercise phyiologists understand that athletes are able to build aerobic capacity (so-called VO2 max) by exerting themselves at or near maximal heart rate.  Their state of fitness is manifest in a reduced resting heart rate or pulse, and a higher ratio between peak VO2 and resting VO2.  This ratio or difference is sometimes referred to as VO2 reserve or VO2R, and it represents a good measure of aerobic fitness, a kind of dynamic capacity to oscillate between rest and exertion. Yet another measure of dynamic capacity is the rate at which heart rate or VO2 return to normal, after exertion

What is interesting is that training harder does not necessarily increase VO2R or dynamic capacity.  A study by the Navy Seals showed that overtraining can actually decrease VO2R, and can elevated resting heart rate by as much as 10-15 beats per minute.  Monitoring your resting heart rate is an excellent way to know if you are overtraining.  (Caveat: the heart rate measure must be used with judgement, as severe overtraining can lead to extreme exhaustion and an abnormally low heart rate).

More generally, high intensity interval training (HIIT), whether it be in the form of weight lifting, sprinting, or other metabolic training, is based on the very same premise.  Maximal exertion, into the anaerobic range, activates the full range of muscle fibers, including the ever-important fast-twitch muscle fibers, empties muscle glycogen, and activates the glycolytic pathway, resulting in an upregulation of insulin receptors (GLUT4 transporters), and improved insulin sensitivity.  But for HIIT to work effectively, it is equally important to allow adequate time for rest and recovery.  (I’ve discussed this in more detail on the Fitness page of this blog, with particular emphasis on the physiological analysis of Doug McGuff in his book, Body by Science).

For sports as varied as running and weight lifting, the well known principle of periodization recognizes the importance of variation in intensity and proper rest. In short, both high intensity training and aerobic training, if carried out with adequate rest and recovery, build dynamic range.

Example 2.  Digestive or metabolic fitness can be measured by a low basal insulin level in combination with a pattern of sharp, but brief insulin secretion in response to ingested carbohydrates or insulinogenic protein.  Low basal insulin level is seen, for example in non-industrialized populations such as the Kitavins, whose average basal insulin levels of about 4 mIU/ml are about half those of Western populations.  And yet the Kitavans consume meals with a high percentage of carbohydrates and have good insulin sensitivity.   So low basal insulin levels alone are not the whole story. The optimal pattern seems to involve an alternation between feast and fast, allowing the digestive hormones and enzymes to cycle between anabolic (insulin) and catabolic (glucagon, adrenaline, and cortisol).

This is also the premise behind the concept of intermittent fasting.  By training yourself to cut out snacks and go for longer periods of time between meals, the metabolic system — which includes not only digestive hormones and enzymes, but neurotransmitters and hypothalamic receptors — adapts to increase its dynamic capacity.  The resulting benefits are lower basal levels of anabolic hormones like insulin and catabolic hormones like glucagon and adrenaline. But just as importantly, intermittent fasting develops improved sensitivity and the ability to both ramp up and reduce these hormones quickly and responsively.

The benefits of spending time in the fasting state are numerous, including a natural detoxification and nutrient recycling process known as autophagy, and the upregulation of brain-protective growth factors such as Brain-Derived Neurotrophic Factor (BDNF).  Fasting allows for the upregulation of fat-liberating enzymes and hormones and a significant and glucose transporters, thereby improving insulin sensitivity. McEwen has compiled research showing that an appropriate level of “stress” or allostatic load will increase markers of brain plasticity. By contrast, following the conventional wisdom to eat six small meals a day of controlled glycemic foods, in the misguided attempt to “regulate” blood glucose at a constant level, deprives your body of these important restorative and protective processes.

But at the other extreme, extensive fasting or strict low carbohydrate dieting can leave the pancreas underutilized and thereby lead to a reduction in glucose transporters in the cells, since these are no longer “demanded”.  Our cells and organs tend to “economize” by synthesizing only the machinery they really need: use it or lose it.  People who abstain from or never consume milk will lose the ability to produce the enzyme lactase, so they become lactose intolerant.  Similarly, we need to regularly “exercise” our ability to secrete insulin on demand and the ability of cells to utilize glucose. This doesn’t necessarily have to occur every day, but several glucose loadings a week are probably necessary.

So the wise course is to apply “stress oscillation” to diet, and alternate judiciously between fasting and nutritious, balanced meals with a variety of macronutients and micronutrients.   Remember that the “stress” is binary: fasting represents recovery from the “stress” of eating; and eating relieves the “stress” of fasting.   A dynamic approach of hormesis involves stretching the ability to move between these two poles, increasing “allostatic capacity”.

Example 3.  Stress, health and cortisol.  Of all the hormones, cortisol has acquired a reputation as “the bad guy”.  It is well known that elevated cortisol levels are the mark of chronic stress and adrenal fatigue.  It has been suggested that higher levels of cortisol are linked to disregulated or high blood glucose levels and predispose one to diabetes. Chronically elevated cortisol also damages neurons in the hippocampus, leading to memory loss and cognitive decline. As a result, some practitioners mistakenly advise trying to minimize stress and even eat frequent meals, in order to keep cortisol at bay and avoid “stressing” the adrenal glands. But this is a one-sided perspetive.  Cortisol is necessary to normal alertness and mental function, as well as our ability to respond to sudden demands like exercise or threats. The problem comes when cortisol does not exhibit a normal morning peak level, followed by a steady decline through the day, but instead remains flat or even increases in the evening.  Chinook et al. classified four different cortisol patterns, shown below.  Pattern 1 (Graph A) is normal; Patterns 2, 3 and 4 show the flattening or later peaks that characterize dysregulation:

Diurnal or event-related elevations in cortisol are not problematic, so long as cortisol levels return to baseline at a decent rate, as in Pattern 1. According to Lovell et al., higher percieved stress levels are reflected not so much in average cortisol levels, but rather as higher basal or evening cortisol levels, and flatter diurnal fluctuations in cortisol levels. Matthews et al found that individuals with the flattest cortisol pattern (slowest rate of decline to baseline) were most at risk of coronary calcification.  Sephton et al found that flatter cortisol patterns were predictive of suppressed immunity and lower survival rates in women with metastatic breast cancer.

In short, we should be less concerned with absolute cortisol levels, than with the pattern of cortisol secretion.  As with other hormones, increased dynamic range and a robust cyclical pattern are indicative of fitness, stress-hardiness, and health.

The larger lesson.  James Loehr (about whom I wrote in my earlier post on Stress management and toughness training) has written eloquently about the use of “stress oscillation” to build athletic capicity and resilience in the corporate world in his book The Power of Full Engagement:

Balancing stress and recovery is critical not just in competitive sports, but also in managing energy in all facets of our lives. When we expend energy, we draw down our reservoir. When we recover energy, we fill it back up.  Too much energy expenditure without sufficient recovery eventually leads to burnout and breakdown…Too much recovery without sufficient stress leads to atrophy and weakness….Oscillation occurs even at the most basic levels of our being. Healthy patterns of activity and rest lie at the heart of our capacity for full engagement, maximum performance, and sustained health. Linearity, by contrast, ultimately leads to dysfunction and death. (TPOFE, pp. 29-31).

How to apply stress oscillation to your life. Let’s return to the question at the beginning of this post: How much of any kind of stress is enough, but not too much, to generate a hormetic benefit? The answer is: This is the wrong question!  You should not be striving for some magic optimum level of constant stress. Rather, you should strive to oscillate stress, by exposing yourself to intermittent, but intense sources of stress.  This builds dynamic capacity or strength. The amount and frequency of the stress are variables you can experiment with, but younow have a way to measure the benefit and know whether you are on track. The key metric is dynamic capacity. The appropriate measures of dynamic capacity depend upon what our goals are:

• For physical fitness:  a high VO2 max during exertion combined with a low resting VO2, resting pulse, and blood pressure.
• For dietary or metabolic health:  a rapid insulin and blood glucose response to food and low basal insulin and blood glucose levels
• For stress hardiness:  peak cortisol levels upon waking, followed by steady decline to low evening (basal) levels.

These may be imperfect measures, and they are subject to exceptions and interpretations based upon special health circumstances. Some of these measures are easy to implement at home; others are less convenient because they require blood or saliva analysis (which can be purchased online). But the general principle is valid:  Don’t look for average biometric values, but look for the dynamic range between high and low. And look for an oscillatory pattern that demonstrates periods of testing and building capacity, alternating with periods of rest and recovery.  I’ve discussed only three applications here in detail: digestion, exercise, and general stress tolerance.  But the principle of stress oscillation can be applied to many other applications of hormesis:  suntanning, allergen immunotherapy, cold showers or plus lens therapy.  I leave it to the curious reader to think about the physiological processes at work, and the appropriate measures of improved dynamic capacity.

The goal of hormetic stress should be to increase dynamic capacity to handle allostatic load — variable stresses — in a measureable way.  The precise level and frequency of stress exposure will vary from person to person. This is not a one-size-fits all path to health, but rather a journey that each of us must take for ourselves.  But on this journey, our engine is stress oscillation and our compass is increased dynamic capacity.

The remedy I want to discuss here is called Sleep Restriction Therapy (SRT). I credit Derek Haswell for bringing SRT to my attention. A 4-8 week course of treatment has been shown to be very effective in restoring normal sleep. The basic idea behind SRT is to limit your sleeping in a controlled manner until it renormalizes. As with any application of hormesis, the solution may at first seem paradoxical:  to combat a stress you should apply judicious amounts of that very stress to train the mind or body to adapt. It works for building muscles, improving eyesight, normalizing appetite, and improving immunity.  And sleep therapists have now found a way to use hormesis to improve the quality of sleep.

The protocol. Here is how Sleep Restriction Therapy works:

1. Determine a fixed time to wake up every morning and set your alarm for that time. This is an absolute requirement: when the alarm goes off you must get out of bed immediately with no snoozing or exceptions.  If necessary, use a loud alarm and put it across the room.  Some researchers find that exposure to bright morning light upon waking is important to the success of SRT.
2. Determine the minimum number of hours you need to sleep. This is usually done by keeping a sleep log for several nights to figure out the average number of hours you are actually sleeping. If you are in bed for 8 hours but are awake for 2 of those hours, then your sleep requirement is 6 hours. In general, the minimum sleep requirment should never be less than 4.5 hours.
3. Do not go to bed or even go into your bedroom until the official bedtime. If your wake time is 6 a.m. and your initial sleep time is five hours, that means you cannot go into your bedroom to sleep until 1 a.m.  You have to keep yourself awake between 6 a.m. and 1 a..m. the next day.  No napping, lying down or nodding off is allowed.  This is difficult and can produce drowsiness and grumpiness during the initial days of treatment.  In some versions of SRT, slightly longer hours are allowed on weekends as a “reward” for making progress.
4. Measure your “sleep efficiency” each night. Calculate sleep efficiency as the hours you actually sleep expressed as a percentage of the total hours you are in the bedroom.  To track sleep efficiency, keep a sleep log — a record of when you go to bed and wake up during the night, noting the related circumstances and activities. Your goal is 90% or better sleep efficiency. An alternative method is to use a home sleep monitor such as that made by Zeo.  The Zeo sleep monitor is an affordable and comfortble “headband” that wirelessly transmits data on your different sleep phases and sleep efficiency to a bedside “alarm clock”, with the ability to view your progress on your PC.  I’ve found the Zeo to be very useful in analyzing sleep patterns.  It reveals the inner workings of your sleep in a way that a manual sleep log cannot.
5. Adjust your sleep time. If your sleep efficiency is greater than 90%, increase your sleep time by moving your bedtime 15 minutes earlier.  If your sleep time is less than 85%, delay your bedtime by 15 minutes.
6. Allow your sleep to normalize. Continue the treatment until your sleep time can be increased to  ”normal” sleep time of 6-8 hours with at least 90% sleep efficiency and subjective feeling of restfulness upon waking and during the day.

Case study. Here is a very compelling video about the success that one British man had using SRT to overcome insomnia:

A study of SRT in 10 elderly patients found that it significantly reduced both sleep latency (time to fall asleep) and subsequent waking during sleep. And the benefits were still in place 3 months after ending the therapy. SRT appears to be effective for most types of insomnia, except for sleep disturbances related to depression, bipolar disorder, sleep apnea or circardian disorders resulting from, e.g., shift work.  One of the immediate benefits that patients note is the reduction of “anticipatory anxiety” — the time and concern spent worrying about what the night will bring.  Many insomniacs see their bedroom as a prison or place of dread.  SRT very quickly compartmentalizes that anxiety. Once they begin to bank 5 or 6 good hours of sleep each night, the progress itself helps to dissipate the anxiety, which in turn tends to make for better sleep.

As with any application of hormetic stress, SRT at first involves “one step backward” by seeming to make things worse.  And indeed the first few days may bring increased drowsiness, while the benefits take weeks to become evident.  The reality is that our bodies adapt often slowly, over a period of weeks or longer.  And so it is with SRT.  But once patients begin to adapt to the new sleep regimen, the quality of their sleep usually improves markedly.  Several weeks of drowsiness and irritability seems a small price to pay for a cure that lasts.

Why does it work? Looked at from a behaviorist perspective, SRT is a form of behavior modification based upon stimulus control. Because patients are truly much more tired when they are finally allowed to climb into bed, the association between the action of getting into bed and the response of falling asleep is strengthened, and the association with “tossing and turning” is weakened.  Undoubtedly, at the level of neuropeptides and receptors in the hypothalamus, SRT must be restoring a  functional homeostasis.  The neuronal pathways, transmitters, and receptors involved in sleep regulation are quite complex.  The ascending arousal system located in hypothalamus interacts with sleep-active neurons in the ventrolateral preoptic nucleus (VLPO) producing a “flip-flop switch” that produces distinct sleep-wake states with abrupt transitions.  The sleep disruptions characteristic of insomnia are believed to involve an excess of corticotropin-releasing factor (CRF) secreted by the hypothalamic-pituitary-adrenal (HPA) axis.  This results in excess production of the hormones ACTH and cortisol, leading to hyperarousal.  It appears that Sleep Restriction Therapy quiets the HPA, leading to improved sleep.

Regardless of the underlying mechanism, Sleep Restriction Therapy appears to be an excellent example of hormesis, a chemical-free way to teach your body to adapt, by exposing it to controlled doses of the very same stress than you want to tolerate more effectively.

It is because I’ve found intermittent fasting to be an attractive practice, both scientifically and personally, that I was so excited to be invited to give a lecture on IF at The 3rd Door, an innovative health and fitness studio, cafe and social center in downtown Palo Alto. The fitness director at The Third Door, Johnny Nguyen, is himself an advocate and practitoner of IF, which he blogs about with great flair and common sense at The Lean Saloon. The talk gave me an opportunity to reframe intermittent fasting in the terms of the philosophy of Hormetism, or applied hormesis that I write about on this blog.  I believe that the framework of hormesis helps to make sense of why IF works, and why it is so much more than a diet.

What follows is a video of my talk on the benefits of intermittent fasting, presented on May 18, 2011 at The 3rd Door.  I would like to thank Dianne Giancarlo and Johnny Nguyen for inviting me to speak, Vaciliki Papademetriou for technical assistance, Francesca Freedman for introducing me to The Third Door, Tom Merson for the still photos and Ken Becker for the masterful video production.

The talk is divided in to five sections for ease of viewing.  It was followed by a 30 minute question and answer session, which I will upload as soon as the video production is complete:

Part 1:  The benefits of calorie restriction

Part 2:  Calorie restriction and hormesis

Part 3:  Intermittent fasting and diet myths

Part 4:  How intermittent fasting turns you into a “flex fuel vehicle”

Part 5:  Practical advice on how to get started with intermittent fasting

Within the coming week, I will add here a recording of the 30-minute question and answer session following the talk.

If the above talk was of interest, you can find more detailed information in two of my other posts:

• Calorie restriction and hormesis
• Learning to fast

Happy fasting!

Many people take daily supplements that include antioxidants such as Vitamins A, C, and E; beta carotene, coenzyme Q10, and alpha lipoic acid. I used to be one of them, convinced of the theory that supplementation with antioxidants is an effective way to neutralize harmful free radicals.  These free radicals, also called ROS or “reactive oxygen species”, can cause oxidative damage to cells and organs, and have been implicated in the pathogenesis of degenerative diseases such as cancer, heart disease, and Alzheimer’ disease.

However, study after study not only fails to show a consistent benefit, but in many cases documents positive harm from taking antioxidants. While I continue to believe that antioxidant supplementation is helpful in certain isolated cases of acute infection, tissue damage, or a damaged or aged metabolism, for most of us antioxidants are probably worthless. In fact, antioxidant supplements can interfere with and weaken the body’s inherent ability to mount an effective defense against oxidative damage and its contribution toward degenerative diseases.

I’ve resisted this conclusion because I could not make sense of it.  That is…until I came across recent research into the biochemistry and genetic regulation of the antioxidant response element (ARE). Fortunately the ARE provides us with an in-built adaptive stress response that combats oxidative stress and inflammation The ARE makes the need for antioxidants in the diet unnecessary — other than to keep our food fresh. Surprisingly, antioxidant supplements can impair our adaptive stress response.  But there’s much we can do to strengthen this response.

Fruits, vegetables and green tea. One of the strongest arguments for taking antioxidant supplements is the observation that consumption of fruits and vegetables reduces the levels of oxidative damage and associated degenerative diseases. This has been shown in both epidemiological studies and observational studies.  Similar benefits have been associated with the consumption of certain herbal compounds rich in polyphenols, such as green tea, garlic and curcumin.  The assumption has always been that these benefits can be attributed to the fact that many fruits, vegetables and herbs are rich sources of naturally occurring antioxidants. Therefore, it only makes sense that if you can’t get enough fruits and vegetables in your normal diet, supplementation with purified chemical forms of these antioxidants can boost those benefits.  But it turns out that the protective effects of fruits and vegetables are most likely not due to their antioxidant content, which is probably too weak and inconsistent to explain the health benefits.

But before discussing the real reason that fruits and vegetables have health benefits, let’s review what is known about supplementation with antioxidants.

Antioxidant supplementation studies. It may surprise you that numerous of clinical trials and metabolic studies show no benefit, or even harm, from using antioxidant supplements:

• A 2004 American Heart Association meta-analysis of 20 clinical trials showed no benefits for the use of Vitamins C, E and beta carotene in the prevention of heart attacks or strokes, and no reduction in mortality.  While they acknowledged that the scientific evidence from observational studies supports the conclusion that “a diet high in food sources of antioxidants and other cardioprotective nutrients” reduces the risk of CVD, they found no support for any benefits from the use of antioxidant vitamin supplements.  They did indicate that antioxidant supplementation may be useful in certain critical medical procedures, but not for routine dietary supplementation.
• A 2008 Cochrane Institute meta-analysis of 67 randomised clinical trials on antioxidant supplements (beta-carotene, vitamin A, vitamin C, vitamin E, and selenium) versus placebo or no intervention found no evidence that antioxidant supplements prevent mortality in healthy people or patients with various diseases
• A University of Washington randomized trial showed evidence of positive harm from antioxidants.  A cocktail of antioxidants added to the course of patients with high cholesterol and using statin-niacin therapy led to reduced levels of HDL and increased levels of coronary blockage .
• A Kansas State University study showed that administering antioxidants during exercise can impair muscle function by suppressing hydrogen peroxide, a key signaling compound.  This can lead to reduced blood flow in the muscle.
• A study at Cedars-Sinai Heart Institute showed that cardiac stem cells cells that were loaded with high doses of antioxidants developed genetic abnormalities that predispose to the development of cancer.
• A study comparing chemical Vitamin C with oranges containing an equivalent amount of Vitamin C given to test subjects showed that the blood from those who ingested the oranges could neutralize hydrogen peroxide (an oxidant) but those who ingested Vitamin C tablets failed to do so.

These results were at first puzzling to me.  How can it be that administering the same antioxidant chemicals ubiquitous in “protective” fruits, vegetables and herbs — the same chemicals which have been shown to neutralize oxidants in the test tube — appear to be ineffective or even harmful when taken as dietary supplements? What’s going on here?

The endogenous antioxidant defense. What is missing in the above picture is the role of our body’s own innate defenses system for handling toxic chemicals like free radicals. While our immune system handles invading organisms and large proteins, another system is needed to deal with chemical toxins. It’s called the xenobiotic metabolism; “xenobiotic” is Latin for “foreign to the organism”.  It consists of three “waves” of protective enzymes which neutralize dangerous chemicals, designated: Phase I, Phase II, and Phase III.  In Phase I the “xenobiotic response element” (XRE) chemically modifies the foreign toxins, which can sometimes make them even more reactive oxidants.  In Phase II, a set of antioxidant enzymes known as the “antioxidant response element” (ARE) neutralizes these toxins, including free radicals. Phase III involves further modifications and excretion.

The ARE is your body’s own endogenous antioxidant defense.  And it is far more powerful and effective than any antixodants you consume orally at mounting a defense against free radicals.  The ARE system is activated by the presence of oxidants in specific tissues in the body. These oxidative toxins are detected by transcription factors, most importantly Nrf2 (Nuclear factor (erythroid-derived 2)-like 2).

Nrf2 has been called the “master redox switch”.  It turns on a series of cytoprotective genes, which have been nicknamed “vitagenes” by U. Massachusetts toxicologist and hormesis researcher Edward Calabrese. These vitagenes upregulate the production of endogenous antioxidant enzymes that combat oxidative stress and inflammation. Collectively, they are known as the Phase II antioxidant enzymes:

• glutathione transferase
• glutathione peroxidase
• glucuronysyl transferase
• quinone reductase
• epoxide hydrolase
• superoxide dismutase
• gamma glutamylcysteine

So how can it be that supplementing with antioxidants can actually dampen the body’s internal antioxidant defense system?

Homeostatic compensation. As we’ve seen time and again in this blog, the body is an adaptive system.  The organism adjusts to maintain a relatively constant state: homeostasis. Provide it with external “help” and it will reduce the effort in building its own internal defenses.  Just as using corrective lenses will weaken the eye’s inherent ability to focus, and avoiding exposure to allergens will prevent the adaptive immune system from developing, it turns out that chronic consumption of exogenous antioxidants reduces the “pressure” on your adaptive stress response — specifically your ARE system — to gear up its own endogenous antioxidant defense system by producing adequate amounts of the the Phase II enzymes.  In biological terms, taking antioxidants leads to homeostatic downregulation of the antioxidant response element.  This actually makes biological sense:  Why should the organism expend precious energy and resources building a defense system if the defense is provided for “free” through diet or supplements?

A number of studies bear out this compensatory effect:

• A metabolic study in houseflies showed that administering Vitamin C (ascorbic acid), Vitamin E (alpha tocopherol) and beta-carotene caused a compensatory depression of  activity of key endogeneous antioxidant enzymes includiing superoxide dismutase, catalase, and glutathione. The administration of vitamins C and E also reduced life span. Granted that humans are not the same as flies, but we use the same enzymes to detoxify.
• A study of supplementation of cells with the antioxidant lipoic acid showed that it inhibits the antioxidant adaptive response triggered by treatment with UV-B light  The added lipoic acid decreases the intracellular oxidative signals necessary to develop the adaptive response in human mononuclear cells.
• A 2008 study at the University of Valencia showed that  Vitamin C supplementation hampered exercise endurance.  While Vitamin C reduces ROS levels in short term, it impairs the adaptive response by reducing transcription factors that enable mitochodria production, and inhibiting expression of antioxidant enzymes superoxide dismutase and glutathione peroxidase.
• A 2010 study showed antioxidants can cause neurodegeneration by inhibiting autophagy — an important process for removing damaged cellular material.  Inhibition of autophagy by antioxidants has a range of other potential negative consequences.

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.

But if the endogenous antioxidant defense system is so potent, what steps can we take to build it up?

Plant toxins to the rescue. Nature exhibits a wonderful phenomenon called “biological arms races”.  To defend against predators, plants or animals develop defenses, and often this involves the production of biological “poisons”.  To defend themselves againts pests and parasites, plants have evolved a set of mildly toxic substances that discourage, sicken, or even kill predators, from microbes and insets to mammals.  These toxic substances typically taste bad and can be irritating.  However, predators evolve to be able to tolerate at least some of these plant toxins, at least in moderate amounts.  They do this by developing detoxification systems.  Which is exactly what the ARE is!

Some plant toxins are too poisonous and deadly.  But, as Nietzsche said: “That which does not kill us makes us stronger”.  Biologically speaking, this is the principle of hormesis advocated on this blog, the principle by which small amounts of a stressor activates and strengthens our internal defenses, but excessive levels of the same stressor overwhelms these defenses.  Our ARE anti-toxin system will develop in response to virtually any toxic compound.  In principle, you could strengthen it by ingesting all kinds of chemical poisons. But why play roulette?  Humans have grown up for eons consuming a fairly regular supply of certain plants to which they have become habituated, plants that contain tolerable amounts of toxins which moderately stimulate the adaptive stress response, but not sufficiently to kill us.  Of course, there are still poisonous plants and mushrooms which exceed this threshold, so there is a continuum.  And probably some people and populations can tolerate more than others of certain plant toxins. But some of these plant toxins are well enough tolerated by most of us to prove reliably beneficial.

What are the good plant toxins? We refer to them as “phytochemicals” or “phytonutrients”.

There are a nearly infinite number of phytonutrients, most of them unknown and uncharacterized.  But a number of them have been studied for their impact on upgregulating the Phase II enzymes of the the ARE system, as Mattson et. al. have detailed..  Many of these compounds fall into the chemical class of polyphenols, more specifically flavonoids.  They are typically pigmented, bitter or spicy tasting molecules. A partial list includes:

• resveratrol – from red grapes, which turns on sirtuins and has broad cardiovascular, memory and anti-aging benefits
• sulforaphone – from broccoli, which turns on antioxidant and anticancer enzymes in the skin, arteries and stomach
• curcumin – from tumeric, inhibits transcription factors and kinases involved in cancer and inflammation
• green tea - a rich but variable source of bioflavinoids which have been shown to have anticancer and cardioprotective effects

Other polyphenolics that stimulate that Phase II enzyme system have been found in garlic, rosemary, ginko, bee propilis, and even…coffee!

What may have confused many researchers is that these polyphenolic flavonoid compounds in many cases have antioxidant properties.  This fact may have led to drawing the mistaken conclusion that they work because they are antioxidants in their own right.  And yet this antioxidant effect is not consistent — polyphenols and other phytochemicals sometimes function as pro-oxidants, dependent on the context and dosage.  I believe the evidence for their being hormetic stimulants of the endogenous ARE system is stronger than the case for thinking of them as antioxidants.   For example:

• A review of cell culture experiments with various polyphenols shows that their mechanisms of action goes beyond their intrinsic antioxidant properties, by indirectly stimulating enzyme transcription through the ARE system.
• Resveratrol seems to have its optimal effect at concentrations too low to be explained by an antioxidant effect. A metabolic study of resveratrol in heart cells, showed that even at very low (micromolar) concentrations, it upregulates endogenous “cytoprotective factors” — antioxidants and phase 2 enzymes such as superoxide dismutase, catalase, glutathione, glutathione reductase, glutathione peroxidase, glutathione S-transferase (GST), and NAD(P)H:quinone oxidoreductase-1 (NOQ1).
• An Israeli study showed that caratenoids in tomatoes activate the ARE transcription system, upregulating the phase II detoxification enzymes in a manner that is not correlated with the antioxidant potential of the caratenoids.   However, caratenoids appear to have an optimum level, above which they may be harmful.

Am I the only one challenging the paradigm that fruits and vegetables are good for us because they are rich in antioxidants?  Certainly not. Stephan Guyenet has likewise challenged this explanation, and highlighted the hormetic properties of plant polyphenols in an excellent two-part series on his Whole Health Source blog:

• Polyphenols, Hormesis and Disease: Part I
• Polyphenols, Hormesis and Disease: Part II

In his article, Guyenet mentions the interesting phenomenon that the hormetic effects of polyphenols tend to be non-specific:

One of the most interesting effects of hormesis is that exposure to one stressor can increase resistance to other stressors. For example, long-term consumption of high-polyphenol chocolate increases sunburn resistance in humans, implying that it induces a hormetic response in skin. Polyphenol-rich foods such as green tea reduce sunburn and skin cancer development in animals.

Another researcher who has come to similar conclusions as me is Robert Rountree.  If you had trouble following the science here and you have 90 minutes to spare, please do yourself a favor and click here listen to this extremely informative, lucid, and humorously entertaining lecture by Rountree that was presented at the 2010 Integrative Healtcare Symposium.  Unfortunately this is an audio recording so you’ll have to just imagine the slides, but not much is lost without the pictures because Rountree is such a vivid speaker:

CLICK HERE TO LISTEN:

“Beyond Antioxidants: Nutrigenomic Regulation of the Adaptive Stress Response“

by Dr. Robert Rountree

Rountree makes the very powerful point that the skin-protective effect of the sulforaphane in broccoli cannot be explained by its inherent chemical antioxidant properties. He cites a Johns Hopkins study in which broccoli extract applied to the skin of nude mice prevented oxidative damage from UV light for a period of several days, even after it was washed off the skin.  The absorbed sulforaphane could only act as an antioxidant for 30-60 minutes, at best a short-term effect. However, the induced upregulation of antioxidants in the skin protected the skin from UV for two days! To put it in chemistry terms: antioxidants are stoichiometric and used up quickly, whereas the endogenous antioxidant enzyme system is catalytic and long-lasting.

I’ll conclude by considering three interesting questions:

1. Why are there antioxidants and polyphenols in plants, vegetables and herbs?

Rountree suggests a plausible reason for why plants are rich in polyphenols: they act as natural pesticides. As I suggested above, this is part of the evolutionary arms race, and we’ve at least partially adapted to tolerate certain levels of these natural plant toxins.  But what about the antioxidants?  They don’t seem to protect the plant from predators, so why are they there?

I think the most plausible evolutionary reason for the presence of the antioxidants in plants is to protect the seeds in the fruit or vegetable against oxidative damage.  But this doesn’t take much antioxidant, as vegetables and fruit are relative “static” seed protectors.  They aren’t dynamic organisms requiring a long term sustained defense, as is the case with animals.

2.  If antioxidants are useless or even detrimental to our endogenous antioxidant defenses, should I take vitamins?

This is not a simple question, and I’m not your medical practitioner.  But a few things can be said here. First, antioxidant vitamins like Vitamin C (ascorbic acid) and E (tocopherols) are not merely antioxidants. They also perform certain other essential biological functions in processes such as collagen synthesis (Vitamin C), preventing scurvy, and protecting against lipid peroxidation in membranes. However, for these functions only very low amounts of the vitamin are required. By some estimates, 10 mg per day of Vitamin C will prevent scurvy, and 4 mg per day of Vitamin E will ensure good membrane function. The multi-gram  megadoses recommended by advocates of “orthomolecular medicine” such as Linus Pauling are based upon the antioxidant function of these molecules. In light of the studies showing that high levels of exogenous antioxdants suppress our innate endogenous Antioxidant Response Element, these high levels seem to me to be uncalled for, and likely to impair our native ability to handle oxidative stress.  The only exception I would make is in the case of acute or severe infection or illness, or advanced age, where the body’s own immune system and xenobiotic defense system may be compromised or unable to mount a sufficient defense on its own. But routine daily supplementation with antioxidants seems unwise if you are otherwise healthy and eat a good diet.

I’m also only addressing here the antioxidant vitamins and minerals, so this discussion is silent as to the wisdom of supplementation with other vitamins, such as Vitamins A, B and D, which are not classically considered to be antioxidants. Yet I think the general principle of hormesis should always be considered: that which is beneficial at a low or moderate dosage is often detrimental at higher doses. So be careful.

3.  What dietary guidelines can I follow to strengthen my endogenous antioxidant defense system?

What is most exciting for me is that I think I finally have a scientific reason to eat more and varied vegetables, fruits, herbs and spices! Coming from a generally low carb orientation, I’ve made sure to get plenty of protein and fat in my diet from meat, fish, dairy and nuts.  I happen to like broccoli, asparagus, brussell spouts, green and red peppers, and mushrooms, strawberries and blueberries.  But I always thought of them as something to liven up a low carb / Paleo diet with variety, texture and flavor, and perhaps add a little fiber.  I had heard the benefits of “phytonutrients” touted, but never heard a solid scientific reason for their nutritional value.  Thinking of them as hormetic “plant toxins” that help strengthen our internal defenses puts them in a new light.  This suggests a few guidelines to maximize hormetic stimulation of the ARE Phase II enzyme system:

• eat especially those vegetables and fruits with bright or intense colors (these contain bioflavonoids)
• eat fruits, skins and seeds which are bitter (these contain glucosinolates)
• consume teas, herbs and spices which have strong, bitter, or hot flavors
• to ensure hormesis, vary your choices, and limit the amount and frequency of any single fruit, vegetable or herb

Finally, consider the activation of your in-built detoxification system — your ARE — as just one element of your adaptive stress response capability, which more broadly extends to your immune,  endocrine, nervous, and musculo-skeletal systems, and at a higher level — your psychology and spirit. The more we probe, the more it becomes apparent that we have within ourselves the ability to strengthen our defenses and take on increasing challenge. Relying on external supplements and external crutches is unwise except in the short term. The role of nutrition should be to build us up, not to replace — and thereby weaken — our internal defense, repair and growth capacities.

Do you have allergies? Are you sensitive to certain foods or chemicals?  If so, you are part of an epidemic explosion in the incidence of allergies and sensitivities in the U.S. and Western societies. The allergy epidemic is frequently blamed on the profusion of pollutants and toxic man-made chemicals in modern industrial society.  And the conventional medical approach to dealing with allergies is to avoid exposure to allergens, and to block allergic reactions by using antihistamines.

But there is an alternative explanation and a more effective treatment, consistent with the theory of hormesis.  The explanation is called the hygiene hypothesis and the treatment is called allergen immunotherapy.  I’ll discuss these both shortly, but first let’s look at what is really behind the outbreak of allergies in the modern world.

The allergy explosion. In his book “Why Things Bite Back: Technology and the Revenge of Unintended Consequences“, Edward Tenner noted that hay fever was virtually unknown in the year 1800.  But by the end of the nineteenth century, hay fever and other allergies had become widespread.  Yet, according to Tenner, this did not seem to be a consequence of industrialization or urbanization per se:

In fact, as hay fever and other allergies multiplied in the nineteenth century, it was not working class children growing up amid industrial haze but instead the scions of the best households that were affected. Epidemiologists are beginning to believe that large families, messy play, and early infections could have helped condition children’s immune systems not to gear up against a common substance like pollen when they first encountered it.  The protein that mediates hay fever, IgE, appears designed to defend the body against worm infestation. The allergist and historian Michael Emanuel has speculated that hay fever results from IgE deprived of its original target, noting that “man evolved with his parasites and their may be a price to pay for their removal.” (WTBB, pp. 102-3).

More recently, over the past several decades in the U.S., the prevalence of atopic dermatitis  in children has skyrocketed. A high percentage of these kids go on to develop full-blown allergies and asthma.  And paradoxically, wider use of medication to control allergies does not seem to be helping.  According to a 1996 article in Environmental Health Perspectives, citing Peter Gergen of the National Institite of Allergy and Infectious Disease, we are confronted with a disturbing reality:

Trends in Asthma Prevalence, 1982-1993

[D]uring the last three decades, asthma prevalence and morbidity in the United States has been rising. “The paradox of asthma is that we’ve had good treatment and quite adequate medications, and yet we’re still having this problem,” said Gergen… The increase in asthma is not unique to the United States. Asthma appears to be growing worse in other economically developed countries as well.

But the article follows the conventional way of thinking, going on to put the blame on environmental factors prevalent in urban areas:

Spurred by the alarming statistics, researchers are focusing on direct exposures to allergens indoors where people are spending more of their time. Allergen levels are thought to be higher in less well-ventilated homes, where moisture accumulates, allowing mildew and molds to grow. Research shows that cumulative exposure to dust mites, which live in bedding, upholstery, and carpets, causes some people to develop allergic sensitivity, including asthma and airway hyperresponsiveness. The levels of cockroach antigen generally found in suburban homes are too low to sensitize individuals, but the 10-fold higher levels found in inner-city dwellings are enough to cause sensitization and appear to be associated with asthma. ”We’re also concerned about second-hand tobacco smoke,” said Alfred Munzer, pulmonary specialist at Washington Adventist Hospital and former president of the ALA. “There is increasing evidence that childhood exposure to environmental smoke can be a predisposing factor to developing asthma.”

Yet, in contradiction to the above statement about the effects of cigarette smoke, the incidence in allergies has been rising at the same time as smoking is on the decline. Furthermore, exposure to environmental pollutants and indoor allergens like dust mites cannot explain the increase in food allergies.  In fact the rise of food allergies might give us a partial clue:  According to a recent CNN article, there is evidence that the standard Western diet has altered intestinal flora and weakened our immune systems:

A study in Proceedings of the National Academy of Sciences compared the gut bacteria from 15 children in Florence, Italy, with gut bacteria in 14 children in a rural African village in Burkina Faso. They found that the variety of flora in these two groups was substantially different. The children in the African village live in a community that produces its own food. The study authors say this is closer to how humans ate 10,000 years ago. Their diet is mostly vegetarian. By contrast, the local diet of European children contains more sugar, animal fat and calorie-dense foods. The study authors posit that these factors result in less biodiversity in the organisms found inside the gut of European children. The decrease in richness of gut bacteria in Westerners may have something to do with the rise in allergies in industrialized countries, said Dr. Paolo Lionetti of the department of pediatrics at Meyer Children Hospital at the University of Florence. Sanitation measures and vaccines in the West may have controlled infectious disease, but the decreased exposure to a variety of bacteria may have opened the door to these other ailments.

Even establishment allergists like Dr. Hugh Sampson and Dr. Scott Sicherer of Mt. Sinai Medical Center in New York are unable to explain the dramatic rise in food allergies, and are beginning to doubt the advice given to parents to avoid exposing their children to milk, eggs, peanuts, tree nuts, or seafood at a young age.  According to a recent article in the New Yorker:

For most of his career, he believed, like most allergists, that children are far less likely to become allergic to problematic foods if they are not exposed to them as infants. But now Sampson and other specialists believe that early exposure may actually help prevent food allergies. Dr. Sampson recalls that, in 1980, when he started researching food allergies, as a fellow in immunology at Duke University, “I approached the subject with the assumption that I would prove it didn’t exist,” Sampson said. Sampson watched as the incidence of food allergies rose alarmingly in the West while cases remained rare in Africa and Asia.

The hygiene hypothesis.  Observations such as those above have led to an alternative explanation for the mushrooming of modern allergies. The hygiene hypothesis holds that the upsurge in allergies is caused not by an increased exposure to foreign substances, but rather by too little exposure to these allergens, particularly during childhood!  It holds that microbes are our friends; the bacteria and other microorganisms in our gut, on our skin and throughout our bodies protect us from intruding pathogens and foreign substances.  What is more, early childhood exposure to a variety of novel environmental materials — colloquially known as “dirt” — is essential to stimulating, developing and strengthening the immune system. But the modern transition to a more sterile environment has deprived us of both the natural microbial defense system and a mature and robust immune system. The lack of primary microbial and immune defenses leads the body no choice but to activate its emergency backup system: the allergic response.

While modern hygiene and medicine have provided great benefits by controlling or eliminating deadly infectious pandemics like influenza, the plague, and malaria, we may have gone too far with the concept of hygiene.  The current equation of sterility with cleanness or goodness has become a misguided obsession, robbing us of our primary defenses.

The human immune system is complex, and it is impossible to do an adequate job of fully explaining how it works in a short article like this.  One of the clearest, most accessible accounts of the immune system I’ve seen is in a recent book about the hygiene hypothesis: “Why Dirt Is Good: 5 Ways to Make Germs Your Friends”, by Dr. Mary Ruebush.  Ruebush explains that we actually have two immune systems:  the innate immune system and the adaptive immune system. The innate immune system wards off infection from pathogens in a generic, non-specific way, using cells like phagocytes and lymphocytes to physically engulf and remove the invaders. But it is the adaptive immune system that allows us to respond more selectively to very particular invaders without attacking ourselves or “friendly” substances like foods or benign and familiar substances in our environment.  And it is the adaptive immune system that goes awry with allergies, sensitivities…and other immune disorders such as auto-immune disease.  But how does this happen?

Adaptive immunity. Your adaptive immune systems consists of antibody-carrying B cells (produced in your bone marrow) and T cells of two types (Helper T cells and Killer T cell) from the thymus, a small organ in the middle of your chest.  The thymus is like a “school” in which T cells are “educated” to respond to specific external threats.  There is a critical period of the thymus organ in early childhood, during which the adaptive immune system is “educated”; after this critical period the thymus shrivels down in size and becomes less useful.  By means of exposure to a variety of environmental agents during this critical period of our youth, this adaptive immune system puts together an army of specialized “soldiers”:

• macrophages that roam around as “sentinels” throughout the body to encounter invading antigens;
• neutrophils that serve as “foot soldiers”, bringing distress messages back to the thymus;
• helper T cells in the thymus that can recognize the antigen and rapid multiply themselves, sending out legions of reinforcements;
• killer T cells and B cells, the actual antigen fighters that are directed by the helper T cells.  The B cells go after extracellular antigens, whereas the killer T cells attack body’s own cells that get infected with intracellular antigens (e.g. viruses).

The adaptive immune cells (B and T) cells develop normal responses only if they are stimulated by exposure to foreign substances. Most of the B and T cells remain “uneducated” and have a short lifetime and rapid turnover. Only a very few B and T exposed cells become memory cells with a long life time. 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.

Insufficient exposure means an immature immune system. 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. But what is the origin of this strong, misplaced IgE defense? Many immunologists think that the IgE defense most likely originated as a defense against parasites. According to Ruebush,

Parasites are a special problem for your immune system. They are the only category of invader in which the foreigner is actually orders of magnitude larger than anything your immune system has to combat it…Your mast cells hang out just below your mucous surfaces (like in your nose and intestines) and just under the skin. They’re on the lookout for invading parasites…If the mast cells go on the attack against the parasite, they simply explode–they bascially napalm the area. Basophils and eosinophils, the other granulolytic parasite-attacking cells, join in….Allergies are an example of a good immune response gone bad…In developed countries parasitic diseases are no longer common…Overall, this is a good thing…The lack of even a few parasites in your body, however, can be a problem….In the absence of parasites, [the] anti-parasite response can become misdirected against harmless substances in the normal environment. And when your body unleashes an anti-parasite response against something harmless, the damage to your own tissues cause the miserable symptoms of allergies: runny nose, sneezing, hives, diarrhea, and possibly even death by anaphylactic shock.  (WDIG, pp. 79-86)

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.

There is a genetic tendency for children of allergic parents to have allergies, but this can be short circuited through breastfeeding. Babies who are breastfed during the first four months have more IgA antibodies, fewer IgE antibodies and a much lower prevalence of allergies.  After breastfeeding, the next most important step is to expose children to a variety of environments, including different foods, flowers, people, animals, and–yes–dirt and “germs”!

So much for scientific explanations. But what can you, as an an adult, actually do if you have problem allergies? Maybe you missed the boat in childhood and didn’t get sufficient exposure to allergens, microbes or — perish the thought — parasites.  But now you are past childhood.  Is there anything you can do to repair the situation, strengthen your primary adaptive immunity, and dampen your “emergency” IgE allergic response?

The answer is: most likely, yes.

Hormetism for allergies.  Readers of this blog have learned about the principle of hormesis, a broadly validated biological principle by which exposure to modest amounts of stress stimulate an organism’s defense and repair processes, resulting in a net increase in the capacity to face increased levels of the original stress.  Hormetism is nothing more than the systematic, practical application of the science of hormesis in order to strengthen your body or mind in one way or another.  Examples of Hormetism discussed on this blog include:

• high intensity interval training for fitness and fat loss
• plus lens therapy to overcome myopia
• cue exposure therapy to moderate appetite and addictions
• cold showers to stimulate thermogenesis for weight loss and overcoming depression
• philosophical Stoicism to replace negative emotions like fear, anger, or frustration with positive emotions like joy and gratitude.

So is there really a way to apply Hormetism to allergies?  The answer is yes and it follows directly from the hygiene hypothesis, which in effect holds that the development of the human system itself is a paramount example of hormesis.

There are two promising approaches that have been scientifically validated.  The first one is quite interesting, but only for the brave.  The second has been applied for close to a century and is undergoing a recent resurgence with an excellent track record of permanently reducing or eliminating allergies.  I’ll start with the more unusual of the two approaches.

Helminthic therapy. This is a nice name for what others have called, more colloquially, “worm therapy”.  It follows directly from the hypothesis that for most of their evolutionary history, humans co-evolved with parasites.  In the modern area, with the virtual elimation of parasites from the Western world, it is this lack of exposure to parasites that has led to an overactive and inappropriate IgE response.

Helminths are nonpathogenic parasites that are deliberately introduced into patients.  There is a body of research suggesting that helminths can be very effective in rebalancing the immune response, moderating the IgE defense, and thereby reducing or eliminating allergies.  I realize this may seem repugnant to some, but the parasites used are microscopic and benign, not the grotesque tapeworms and bizarre organisms seen in medical textbooks. If interested, there is some useful background and references on the Helminthic Therapy website.

Allegen immunotherapy. The conventional medical approach to dealing with allergies is to avoid exposure to allergens (for example by installing air filters and keeping your carpets clean)  and to disable the immune or inflammatory response by medicating with histamines.  As with many applications of Hormetism, allergen immunotherapy takes a diametrically opposite approach. By exposing the patient first to minute amounts of allergen, and progressively increasing the exposure in a systematic manner, the primary adaptive immune system is strengthened. According to Dr. Adrian Morris, the emergency IgE response is dampened by means of stimulating production of an allergen-specific IgG that blocks the IgE response, and possibly also by modulation of the helper T cell response.  In many ways, allergen immunotherapy resembles vaccination, except that object is not to raise antibodies, but rather to normalize an overactive immune response.  Also known as hyposensitization therapy or tolerization, allergen immunotherapy has been found to be very effective:

Allergen specific immunotherapy is the only treatment strategy which treats the underlying cause of the allergic disorder. It is a highly cost-effective treatment strategy which results in an improved quality of life and a reduction in allergic- and allergen-related asthma, as well as a reduction in days off school/work. Immunotherapy has been shown to produce long-term remission of allergic symptoms, reduce severity of associated asthma as well as reduce the chances of new sensitizations to allergens developing… The benefits of allergen specific immunotherapy are long lasting unlike symptomatic based treatments. Immunotherapy is most effective for pollen, dust, and animal dander allergies, and may help those with asthma.

Lest you think that exposure to an allergy-provoking allergen would be dangerous or set off your allergy, read on:

Even the most allergic individual can tolerate minuscule amounts of an allergen without experiencing symptoms. Immunotherapy commences with the subcutaneous injection of a tiny amount of offending allergen, and gradually increases the dose until the individual’s immune system is essentially ‘retrained’ to tolerate exposure without producing an allergic response. This process is also known as specific immunotherapy.

Clinical methods. The most established method of adminstering allergen immunotherapy in the U.S. is to give allergy shots, starting very dilute, and gradually increasing in potency.  There is an emerging approach that appears to be more effective, faster, and has fewer side effects: sublingual immunotherapy, also known as SLIT.  Minute amounts of the allergy provoking substances are formulated in “allergy drops” that are placed under the tongue. While SLIT is practiced widely in Europe, it is still being evaluated by the FDA and is not yet approved in the U.S.

With both allergy shots and subligual therapy, treatment is usually started a few months before the start of allergy season, to build up tolerance. Typically, treatment must be continued for 3-5 years to be fully effective, and may need to be periodically repeated to maintain tolerance.  If interested, you may want to check out several additional references that give a balanced appraisal of allergen immunotherapy, including this 2000 study in the journal Thorax, and this overview in  WiseGeek which suggests that children in particular may benefit from this approach.

Other applications of immunotherapy. In the introduction, I suggested that immunotherapy may also be effective in treating other immunological “overreactions” including chemical and food sensitivities and auto-immune disorders. There is less evidence and research in these areas, and in order to keep this article short, I’ve chosen not to address these possibilities.  But I think it is worthwhile to follow the research in this area.  If the hygiene hypothesis is true, which I think it is, then the possible applications of “exposure” therapies are numerous and offer great promise.

Share your thoughts on this topic on the Discussion Forum.

One of the most common reactions I get to my advice to try intermittent fasting is:  I could never do that!

Like the Jackson Browne song “Running on Empty,” the word “fasting” often conjures up dire images of starvation and energy deprivation.  Many of you reading this post may have experienced strong hunger pangs, headaches, tiredness, sweating and even shaking or wooziness when going without eating for even part of a day, much less a whole day.  So it is natural to extrapolate such experiences into the thought that going without food for a day, or even several hours, would invariably lead to uncomfortable or even dangerous hypoglycermic symptoms. That, together with the negative image of fasting as something unhealthy or associated with eating disorders, leaves most people pale at the thought of even attempting a short fast.

But I tell you, if you don’t try fasting you are missing out on an enjoyable, incredibly energizing experience that will put you in control of your eating and improve your health, your energy and your outlook.  Many people, myself included, have learned to fast for up to a day or even longer, on a regular basis and without negative repurcussions. Done correctly, short-term fasting is not dangerous, it’s actually health-promoting and greatly helps to retrain your appetite.  If you need to lose weight, the fast helps both in reducing basal insulin and retraining your appetite to be smaller. I’ve written about the benefits of intermittent fasting extensively on this site. Many of the Diet Links listed in the right-hand panel, such as fast-5 and Eat-Stop-Eat, amply document the safety and health benefits of fasting, dispelling the myths about “starvation mode”, slowing of metabolism,  and loss of lean muscle mass.  So I won’t reiterate here the voluminous evidence supporting the benefits of intermittent fasting.  Our bodies are designed to last many days with out food, without great discomfort, and in fact it is beneficial to our health to forgo food periodically. But many of you are asking: Am I really up to this?  How do I get started?

To clarify, by intermittent fasting (IF), I mean forgoing eating for at least 12-20 hours in a day, at least one or two days each week. For many of us, it is a daily practice. Water and unsweetened, non-caloric beverages are allowed, but I exclude “juice fasting” or any solid snacks from true fasting. Others have written about the virtues of juice fasts for “detox” or “cleansing”, but IF has a different purpose, namely insulin reduction, appetite reduction, and mental clarity and focus.

Tips for getting started. So this post is not about the benefits of intermittent fasting, but rather about how to get started with it.  I’m basing this largely on my own personal experience, combined with what I’ve learned about what has worked for others. Fasting is not that hard or unpleasant to do. The reality is that, like skydiving, the contemplation of it is probably far worse than the experience.  You will experience some periods of discomfort, but you may be surprised at how great you’ll feel most of the time you are fasting, especially once you are past the first few hours.  People on low carbohydrate diets often (but not always) experience the pleasurable energy that comes with ketosis; I’ve found that the ketosis of fasting is deeper, and more reliable that that from low carb.  Several people who experience brain fog on low carb  find fasting to provide greater clarity and energy.

Here are 7 practical suggestions to help you get through the transition:

1. Start with a mini-fast. How long do you go between meals without eating? Two hours? Five hours? Start there and try to increase it by a few hours. The easiest way to start is to cut out eating anything between dinner and bedtime. Then go to cutting out afternoon snacks 2 or 3 days a week. And increase from there in increments. Of all my suggestions, I think this is the most important. It’s one of the core principles of using Hormetism to improve your strength and resilience in any challenging endeavor. You have to walk before you can run.

A very common mistake that many people make when embarking on fasting is to go straightaway from a typical pattern of 3 meals per day with snacks, to a day-long fast.  That’s a terrible idea, and yet it forms the main reason that so many people reject fasting as impractical or unhealthful.  I’ll repeat here the comments I made in an earlier post on Calorie restriction and hormesis about a researcher’s conclusions in a 2006 study of calorie restriction in mice, in the journal Biogerontology:

Calorie restriction is doomed to fail, and will make people miserable in the process of attempting it,” said Dr. Jay Phelan, an evolutionary biologist at the University of California, Los Angeles, and a co-author of the paper. “We do see benefits, but not an increase in life span.” Mice who must scratch for food for a couple of years would be analogous, in terms of natural selection, to humans who must survive 20-year famines, Dr. Phelan said. But nature seldom demands that humans endure such conditions. Besides, he added, there is virtually no chance Americans will adopt such a severe menu plan in great numbers. “Have you ever tried to go without food for a day?” Dr. Phelan asked. “I did it once, because I was curious about what the mice in my lab experienced, and I couldn’t even function at the end of the day.

It’s not surprising that Dr. Phelan’s personal “one day experiment” failed and that he “couldn’t function” after suddenly downshifting gears so rapidly. As anyone who has taken the time to research calorie reduction or intermittent fasting realizes, a dietary change of this sort should be approached gradually, allowing time for deconditioning of previous dietary habits and hormonal responses. These changes typically take weeks or longer to become comfortable. But that does not mean that a reduced calorie diet is “extreme”. By historical standards, it would be more accurate to characterize the typical hypercaloric American diet as extreme.

2.  Schedule your fasts. Intermittent fasting works best when you are in control of the timing.  I like being able to spontaneously decide when I’ll start my next fast and I plan exactly when I’ll break the fast and eat.  That really frees me from thinking about food and making choices, because I know that at 4 p.m. Friday or noon Sunday I’ll have my next meal. Associating the start and stop of a planned fast with definite events or times of day takes advantage of the well-known behavioral principle of “putting on cue”.  For a fuller explanation, check out the work of Karen Pryor, the renowned animal behaviorist and dolphin trainer.  I’ve also written about this on the Psychology page of this blog.

3. Cheat using high fat “training snacks”. If you’re having trouble fasting, it is likely that you are lacking the ability to readily shift to fat burning and ketosis.  When you are fasting, after initially depleting your glycogen stores, you will be literally “living off your fat”, as well as fat byproducts like ketones.  To do that, you’ll need to get your insulin level very low and upregulate your catabolic hormones and enzymes: glucagon, adrenaline and hormone sensitive lipase.  But if you are used to eating 3 or more meals and snacking frequently, then you are not used to metabolizing your own fat stores, and you have difficulty shifting quickly from energy storage (anabolism) to energy release (catabolism) .  You literally have weeks of “meals” stored beneath your skin and within your abdomen.  You just can’t access them.  It’s literally like having a locked pantry on your body, so when you get hungry you have to eat food supplied externally, instead of what is already within you.

So train yourself to burn fat by eating pure fat or oil!  The easiest way to train your body to get it used to burning fat, is to “jump start” it with a small high-fat “training snack”.   You don’t need much to get started: 5 to 10 grams of fat is plenty.  Don’t worry, this is not a “high fat diet”, it serves only to provide some satiety and let your metabolism get used to fat burning. The amount of fat you’ll snack on is trivial compared to your overall weekly diet, and you’ll go back to your “normal” diet after the fast. The best approach is to wait until you would normally have a meal or snack and substitute the high fat training snack.  This will tend to suppress your appetite for at least a few hours.  If you start to get hungry again, take another training snack — but wait at least 3-4 hours between these snacks. The training snacks must be virtually free of any carbohydrates or protein and must be small.  Good examples include:

• “Carbless cream soda”. Pour a few tablespoons of heavy whipping cream into a glass (check to make sure it has less than 1 gram carbs) over ice cubes and add sparkling water or herbal tea.
• “Platinum” tea or coffee. To an unsweetened cup of hot tea or coffee, add a tablespoon or two of heavy whipping cream or coconut oil.  The heavy cream has the advantage of easily blending with the tea or coffee, but some people find the coconut oil to be more energizing.  It comes as a solid but readily melts in the hot beverage; it tends leave some oily droplets on the surface because it does not emulsify as well as cream, but most people have no problem with that.  It is important not to add any sweeteners; even artificial sweeteners will tend to psychologically induce a conditioned preprandial insulin response (See Diet page).
• Macademia nuts.  These are high in fat with very few carbs.  Eat no more than a half dozen.
• A small piece of cheese. This is a great training snack, but keep it to one or two small slices of cheese.
• A tablespoon of oil. It may not sound very palatable, but a spoonful or two of extra light olive oil or other vegetable oil can be a great appetite suppressant and kick you into fat burning mode rather effortlessly. The oil works best if flavorless, or if you pinch your nose to avoid tasting it before rinsing.  This is the basis for the popular Shangri-La Diet of Seth Roberts. Roberts attributes the effect to breaking the connection between flavor and calories.  I propose an alternative explanation in my post on Flavor Control Diets.  and also in a long discussion thread on the Shangri-la Diet forum. In any case, flavorless or not, a small dose of oil is a very effective “bridge” to fasting.

4.  Savor flavored calorie-free beverages. To satisfy your need for flavor, enjoy herb teas and black coffee.  Decaf is preferable, but if you have a caffeine habit, go with it for now.  Don’t add any sugar or artificial sweeteners, since these can induce an insulin response that shuts down fat burning. Flavored beverages are a great boon to fasting because they satisfy the urge for flavor and provide some pleasure that can be a big help.

5.  Smell something aromatic while fasting. This is an old aromatherapy trick to turn off your appetite, but it has a scientific basis.  A strong aroma from herbs, spices, flowers or perfumes can rapidly dampen a craving by saturating the cephalic phase insulin response, as explained in my post on Flavor control diets — but you must not eat within 30 minutes after smelling. It is also useful to repeat the smelling frequently and cycle between very different aromas. This has been exploited in devices such as the SlimScents odor inhaler, but a few minutes with your spice rack, perfume bottles or flower garden may do the trick.  The good news is that the effect is long lasting and will permanently decondition your cravings.  Try it!

6.  Drink water frequently. This is an old standby and may seem boring compared to the above two suggestions.  But it works well in two ways: it tends to suppress hunger, and it keeps you hydrated. Keep in mind that the effect is often delayed, so wait 15-30 minutes after drinking the water before you pass judgement on it.

7.  Exercise briefly when hungry or tired. This is one of the more surprising ways to fight cravings, tiredness, mental fog, or borderline hypoglycemia. It may seem counterintuive to expend energy just at the point you are feeling hungry or tired. But it works incredibly well! The key is to do it at the first sign of a cranky or tired feeling, and you’ll head off it off at the pass.  By “exercise” I don’t necessarily mean going to the gym — unless you are used to that. Walking around for 5-15 minutes at a brisk pace is good enough, particularly if you can elevate your heart rate a bit. If you have been fasting, walking or other brief exercise will stimulate your liver to release glucose and free fatty acids, giving you an energy boost. It really is just about as good as eating a meal, for providing energy, and it has the benefit of providing a more sustained form of energy.  You’ll find that “after lunch” meetings are less soporific.

Getting out for a lunch time walk is an excellent alternative to eating lunch.  It gets you away from the kitchen or cafeteria, changes the scene and restores energy.   I probably eat only two lunches a week at work; the other days I go walking either outside or inside, depending on the weather.  Make it social and enlist a friend or start a small walking group – it is just as easy to converse while walking as while eating at a table.

When you get more experienced with fasting, the addition of extended, more intense exercise is very energizing and beneficial. With lower basal insulin levels and upregulated catabolic hormones and enzymes, you’ll find that a long run or workout with weights provides lasting energy and suppresses your appetite. Eating before or after the fast ruins the benefits. Wait at least several hours after the workout before breaking the fast. This may seem paradoxical, as it is virtually the opposite of what many experience who are not used to fasting.  But I have found it to be my experience.  For those interested in fasted workouts, checkout Martin Berkhan’s Leangains blog, as well as a recent article in Running Times on the benefits of glycogen-depleted exercise for greatly increasing your endurance; it appears to be a great strategy for learning to burn fat and weaning yourself off carb dependence,

A final word. The above approach, which emphasizes gradualism, should give your metabolism time to adapt.  For most people, this is enough to avoid any health issues with hypoglycemia or diabetic complications.  In fact, Lee Shurie cured his diabetes, normalized his blood sugar, and increased his energy level by carefully monitoring his blood glucose and gradually transitioning to intermittent fasting.  He found that all the traditional advice to eat low glycemic foods and exercise was insufficient to normal his blood glucose. Eventually, by delaying meal time and allowing his blood glucose to drop into the normal range, he found himself eating only at dinner time, and all the happier for it.  So transition to IF gradually. However, if you have any concerns, stop the fast and eat.  Consult with your physician if you have concerns.  Otherwise, check out the discussion of Intermittent fasting on the Getting Stronger Discussion Forum, to read others’ experiences.

Happy Thanksgiving!

Why is it so hard to make permanent changes to your habits, your health, and your happiness?  Some of the most difficult struggles in life involve losing weight (and keeping it off), overcoming addictions, and recovering from depression. Many diets and therapies deliver great short term results, but the most common pattern appears to be relapse.  It often seems that you are destined to fulfill some biological program — that you are stuck with a high body weight set point or an addictive or depressive personality that cannot be escaped in the long run.

This pessimistic message is prevalent among those who have investigated the track records of the “helping” industries: the weight loss companies, the addiction recovery centers, and the various schools of psychology and psychiatry. Unlike the advocates, those who investigate them often find the results are less than what the practitioners might want you to believe.  In the arena of dieting and weight loss, books such as “The Dieter’s Dilemma” (Bennett and Gurin, 1982), and  ”Rethinking Thin”  (Kolata, 2008) echo the original set point theory first propounded by Gordon C. Kennedy in the 1950s; they conclude that your body weight is largely predetermined by a biological set point that is handed to you at birth, plus or minus about ten pounds. I do agree that sustained weight loss cannot be achieved through sheer will power alone, or simply by using diet and exercise in order to create a calorie deficit. Yet, while there is some plausibility to the set point theory, I am convinced that it is wrong because it overlooks some important factors. I’ve already given some of my reasons for my disagreement with set point theory in other posts on this blog (Flavor control diets, How to break through a plateau). But in this post I’ll present some strong evidence for an alternative theory, based on the homeostatic regulation of cellular receptors for hormones and neurotransmitters. This is a variable set point theory which I call the receptor control theory. This theory proposes a mechanism that controls appetite and body weight, as well as regulating the balance of  energy and pleasure in your life. It provides practical tools to lose weight and keep it off, overcome addictions without relapse, and move out of depression into happiness.

But first, let’s consider some common approaches for dealing with three different  health issues:

1. Obesity/Diabetes. To lose weight, reducing diets are employed that create an energy deficit.  The most effective of these diets work by actively modulating the levels hormones such as insulin or leptin, by modifying the type of food we eat (low glycemic or low carbohydrate are best), or the size and timing of meals.  In the case of advanced diabetes (an insulin deficiency), exogenous insulin is administered periodically in a controlled manner. Alternately, diet pills or other appetite suppressants are used to moderate certain hormones and peptides involved in satiety.  The back-up strategy is to learn how to cope with always being somewhat hungry.
2. Addiction. Addictive cravings from cocaine, alcohol, or other substances or activities have been associated with overstimulated dopamine “reward” circuits.  Some  treatments involve the use of antidepressants to elevate baseline dopamine levels, The back-up strategy is to counsel abstinence to avoid triggering the dopamine circuits in the first place.
3. Depression. To counteract depression, antidepressant drugs (typically SSRIs) are prescribed to boost levels of neurotransmitters such as serotonin or dopamine. Or, we may try non-drug supplements or dietary options to increase the level of these neurotransmitters: for example, serotonin precursors such 5-HTP,  tryptophan-rich food such as turkey and carbohydrates such as potatoes, which allow dietary tryptophan to readily produce serotonin in the brain. The back-up strategy is psychotherapy to provide insight or coping skills to better deal with the underlying depression.

The organic imbalance model. These three seemingly different treatments share a common thread: they are all based on conceiving health problems as intrinsic organic imbalances in our metabolism or neurochemistry that you are either born with or develop early in life, and over which you have little control.   Once you accept this model, there are two basic strategies: an “active” strategy to rebalance internal biochemistry, usually by means of drugs, supplements, or diet. And a “passive” back-up strategy of accepting that you are biochemically different, and counseling ways to cope with these organic conditions as best youe can, while trying to minimize the risk of triggering flare-ups due to relapse, bingeing, or depressive episodes.

Signaling compounds. I’ll focus here more on the “active” interventions which involve trying to directly rebalance the levels of “biochemical messengers” or signaling compounds circulating in our bodies. I’m referring to hormones like insulin and leptin, glucagon, or adrenaline; or neurotransmitters like serotonin or dopamine, which are produced in response to external stimuli.  According to the imbalance model, the levels of these signaling compounds are out of balance: there is a surplus or deficiency of “communication” that needs to be adjusted. The resulting “message” conveyed by the signaling compound is “too loud” or “too soft” for normal bodily function.  So to correct this, a therapeutic intervention is devised which attempts to restore our health by adjusting the amount of the signalling compound in our system.  In effect, the treatment attempts to turn up or turn down the “volume” of the message by adjusting the amount of signaling compound, in order to re-normalize our response to external stimuli.

These active medical or dietary interventions should work, if the imbalance model is correct.  But in many cases the treatments backfire:  after perhaps seeing a short term benefit the effect dissipates, and in some cases symptoms actually worsen, or side effects develop.  After some initial weight loss, the weight is regained.  Attempts to overcome addiction frequently end with relapse and failure. And depression returns. The problem is that we are not mechanical machines, we’re adaptive organisms, regulated by homeostasis. Trying to control message intensity may work for a short time, but the body outsmarts us and compensates for the intervention. Our wonderful, adaptive bodies react to the increased level of signaling compounds by becoming less responsive to them, just as we learn to tune out a dog that constantly barks for attention.  When the message volume is turned up, the receiver volume is turned down.

Our efforts to change seem to be hampered by biological programs that resist these efforts at biochemical rebalancing. Some will explain this by arguing that’s because we are born with a biological set point that our body will “defend” or an addictive or depressive personality that we can’t shake.  Try as we might to fight this in the short term, it’s almost impossible to succeed in the long run.  A lucky few may prevail, but the vast majority are doomed to their biology destiny.

Even if you manage to normalize the level of signaling compounds, you are now stuck with another problem:  you are dependent on some drug, supplement, or special dietary restriction for the long term — maybe even for the rest of your life. Drug companies and dietary supplement suppliers are happy to provide you with a lifetime supply of these compounds for a price.  I don’t know about you, but I’d rather not be dependent long term on drugs or supplements, or even restrictive diets, if it doesn’t have to be that way.

There are grounds for pessimism here.  But there may be a better solution that gives us back control of our fate:  Receptor regulation.

Receptor regulation. Receptors are “message receivers” located throughout our bodies. They are typically transmembrane proteins located on the surfaces of cells, and they bind with hormones and neurotransmitters to “receive” the signal and initiate a sequence of changes in our bodies — often profound system-wide changes in energy utilization, tissue growth, or the perception of pleasure and pain. For some reason, receptors don’t get the public attention that gets showered on the communication chemicals — the hormones and neurotransmitters.  And yet, as I shall argue, the receptors may be far more important than the signaling compounds that they interact with, because they do not change by the minute or hour, but are long-lasting parts of the control systems of our bodies.  If hormones and neurotransmitters are the “software”, receptors are the “hardware”.

The key process to understand is called receptor regulation, the process which controls the number, location and sensitivity of receptors. There are two forms: upregulation (an increase in the number and/or sensitivity of receptors in each cell) and downregulation (the reverse process). Wikipedia explains downregulation by describing how insulin resistance develops in response to elevated insulin levels:

The process of downregulation occurs when there are elevated levels of the hormone insulin in the blood. When insulin binds to its receptors on the surface of a cell, the hormone receptor complex undergoes endocytosis and is subsequently attacked by intracellular lysosomal enzymes. The internalization of the insulin molecules provides a pathway for degradation of the hormone as well as for regulation of the number of sites that are available for binding on the cell’s surface without doubts. At high plasma concentrations, the number of surface receptors for insulin is gradually reduced by the accelerated rate of receptor internalization and degradation brought about by increased hormonal binding. The rate of synthesis of new receptors within the endoplasmic reticulum and their insertion in the plasma membrane do not keep pace with their rate of destruction. Over time, this self-induced loss of target cell receptors for insulin reduces the target cell’s sensitivity to the elevated hormone concentration. The process of decreasing the number of receptor sites is virtually the same for all hormones; it varies only in the receptor hormone complex. (Italics added by me for emphasis).

So not only are the insulin receptors drawn inside the cell (like a turtle into its shell); they are also actively digested and degraded, making them less available to readily redeploy when glucose and insulin levels drop again.  New receptors are always being synthesized, but they are degraded more quickly than they can be replenished if insulin levels remain high. The resulting downregulation of insulin receptors forms the basis for the condition of insulin resistance, in which insulin at normal levels loses its ability to efficiently shuttle glucose from the bloodstream into liver, muscle, brain, adipose or other tissues; the body responds by further increasing insulin, resulting in a vicious cycle of hyperinsulinemia. Reversing this process — growing new insulin receptors — takes time and requires sustained periods with low circulating levels of insulin in order to foster the growth of new receptors.

It is quite revealing to look at how how receptor regulation can undermine “message control” treatments,  due to the way the body adapts. Let’s take a look again at how this plays out in the above three examples of obesity, addiction, and depression:

1.  Obesity. Obesity is associated with high levels of two hormones: insulin and leptin. Normally, an increase in the level of either of these two hormones induces satiety upon reaching the hypothalamus in the brain. Leptin levels in the body increase with the amount of body fat, so leptin has been proposed as a physiological correlate for our “set point” weight: when body fat falls below a certain level, appetite induces us to eat more; when body fat increases, the associated rise in leptin levels leads to satiety. Insulin plays a similar but different role; it tends to regulate appetite on a shorter timescale than leptin, varying during each meal, and is more closely associated with visceral fat of the type more commonly found in men, whereas appetite regulation by leptin operates on more of a daily timescale and responds more closely to subcutaneous fat of the type more common in women. Insulin, of course, is directly involved with the storage and release of metabolic fuels. There are also many other regulatory hormones and sensory peptides, such as ghrelin, CCK and PYY, which adjust appetite based upon meal timing, gut sensations, and other inputs.  But insulin and leptin are key drivers of appetite.

The discovery of leptin, the “satiety hormone” by Jeff Friedman at Rockefeller University in 1993 provoked great excitement and expectations.  A well written account of this discovery is detailed in “Rethinking Thin“, the above-mentioned book by Gina Kolata. Studies in leptin-deficient ob mice and humans showed that individuals with defective production of leptin became ravenous and obese.  So the logical conclusion was leptin itself may be the magical “set point” compound that determines our weight.  Therefore, we should be able to provide leptin to the overweight to help them shed pounds. And in fact, adminstering leptin does work to counteract obesity in mice and humans that are genetically incapable of producing normal leptin, as Kolata describes poignantly in her chapter “The Girl Who Had No Leptin”.  It even works initially in normal or lean mice to reduce body fat. Amgen acquired the rights to leptin from Rockefeller University for $20 million plus royalties in anticipation of imminent commercialization. But after a long-term study in humans, the October 1999 issue of  JAMA reported disappointing results indicating very little weight loss, and even that in only in a small percentage of subjects. As Kolata observes:

The question, though, was, Why didn’t the obese people in Amgen’s study respond to leptin? The possibiity, or perhaps the likelihood, was that leptin was not their problem. These people were making plenty of leptin–they were not the human equivalent of the ob mice. And since adding more leptin did not make them lose weight, it must be that the hormone was being blocked from acting somewhere along its passage from the fat cells to the appetite-controlling pathways in the brain…Then [scientists] discovered that leptin can do something else. It can actually change the brain’s wiring diagram, strengthening circuits that inhibit eating and weakening the ones that spur the appetite. It can exert this effect at a critical period early in life, perhaps influencing appetite and obesity in adults.  And, in adulthood, leptin can again alter the brain’s wiring, permanently changing an animal’s appetite and weight. (RT, pp. 163-165).

The problem is often that excessive sustained levels of leptin, common in the overweight or obese,  can cause “leptin resistance” in which the leptin receptors are downregulated, so that they are fewer in number and become less sensitive to the leptin signal. As Byron Richards indicates in The Leptin Diet:

In overweight people, the communications involving insulin and leptin are inefficient. It is like making a phone call where no one answers. Insulin resistance and leptin resistance mean that the hormones don’t communicate efficiently in response to food. Thus a person has to overeat in order to get enough leptin into the brain to get a full signal. The pancreas may not hear the leptin signal to stop making insulin, which leads to excess insulin, fatigue, and possibly even more hunger within a few hours of eating…Several hours following the meal the extra insulin ends up taking too much sugar out of the blood, making a person hungry and tired-headed. (TLD, p 36)

With leptin resistance, adding more leptin no longer effectively inhibits appetite, because the brain and body have a reduced ability to respond to the extra leptin.  Conversely, lean individuals typically have more leptin receptors and greater leptin sensitivity, so their appetite is satisfied even at reduced leptin levels.  In short, the leptin system adapts so that the number of leptin receptors adjusts to the amount of leptin.

Interestingly, obesity is also associated with reduced number of receptors for dopamine, a neurotransmitter associated with pleasure or reward circuits in the brain. In 2001, Gene Jack Wang and Nora Volkow of the U.S. Department of Energy’s Brookhaven National Laboratory used Positron Emission Tomography (PET) brain scans to look at dopamine receptors in the brains of obese and normal individuals:

Obese individuals, the scientists found, had fewer dopamine receptors than normal-weight subjects. And within this obese group, the number of dopamine receptors decreased as the subjects’ body mass index, an indicator of obesity, increased.  That is, the more obese the individual, the lower the number of receptors.

A 2008 study of women and adolescent girls in New Zealand showed that this receptor deficit is at least partly genetic. The overweight females had the Taq1A1 gene that is associated with fewer dopamine receptors. This receptor deficit in the obese led them to overeat to achieve the level of pleasure or satiety that normal individuals reached with less food. This reduced level of dopamine receptors tends to make life a bit less pleasant for the obese when they are hungry and without food. Ingestion of food, particularly carbohydrates, temporarily raises the level of dopamine, eliminating the “pleasure deficit” and rewarding eating behavior.  Excessive eating or bingeing raises the dopamine levels even higher than normal, which can lead to a further downregulation of dopamine receptors, only worsening the craving problem. This effect is not only influenced by genes, but by diet; a 2010 study of rats fed a supermarket “junk food” diet showed raid desensitization of dopamine receptors a significant increase in appetite, and an unwillingness to return to eating “healthy” food.

The connection between obesity and the number and sensitivity of dopamine receptors is perhaps not so surprising, given how highly rewarding food can be for the obese; for many of the overweight, food becomes an addiction.  It is still quite striking that this translates to such a significant decline in the number of dopamine receptors, while the baseline level of dopamine actually increases.  Here, as with insulin and leptin, we have yet another example of reduced receptor levels being associated with obesity.  By analogy with insulin resistance and leptin resistance, we might say that the strong appetite of the obese is a direct result of “dopamine resistance”.

2. Addiction. What is particularly interesting is that these low levels of dopamine receptors are also characteristic of drug addicts and alcoholics.  Nora Volkow, one of the directors of the Brookhaven study, subsequently became director of NIDA, the National Institute of Drug Abuse. part of NIH, but her research on addiction actually predates the study she did on brain activity in the obese. She used PET brain scans to study dopamine receptors levels in alcoholics, cocaine addicts, and addicted smokers.  And, as you might guess, the same pattern of reduced levels of dopamine receptors was observed in addicts vs. non-addicted controls.  This is illustrated in the PET scan to the right, which shows dopamine binding activity for addicts (top row) vs. non-addicts (bottom row). Regions of greatest dopamine receptor activity are indicated with a color scale starting from red (most active), descending through yellow and green to blue and purple (least active).

The mechanism downregulation of dopamine receptors by cocaine has been elucidated:

Cocaine binds tightly at the dopamine transporter forming a complex that blocks the transporter’s function. The dopamine transporter can no longer perform its reuptake function, and thus dopamine accumulates in the synaptic cleft. This results in an enhanced and prolonged postsynaptic effect of dopaminergic signaling at dopamine receptors on the receiving neuron. Prolonged exposure to cocaine, as occurs with habitual use, leads to homeostatic dysregulation of normal (i.e. without cocaine) dopaminergic signaling via down-regulation of dopamine receptors and enhanced signal transduction. The decreased dopaminergic signaling after chronic cocaine use may contribute to depressive mood disorders and sensitize this important brain reward circuit to the reinforcing effects of cocaine (e.g. enhanced dopaminergic signalling only when cocaine is self-administered). This sensitization contributes to the intractable nature of addiction and relapse.

3.  Depression. A reduced number or sensitivity of neurotransmitter receptors has also been linked to mood disorders such as major depression. Depression has been associated with shortages of at least two neurotransmitters:  dopamine (which is associated with drive, motivation and pleasure), and serotinin (which is associated with a sense of well-being and pleasure).  While dopamine receptors are located largely in the brain, a little known fact is that only about 20% of serotonin receptors are in the brain, most of the other 80% are in the gut, blood platelets, and other organs.  That might help explain why serotonin is also associated with food and satiety.   Different types or depression are often associated with a different imbalance of neurotransmitters, so despite the prevalence of SSRIs, which are intended to restore serotonin levels, some forms of depression respond better to antidepressants which boost dopamine levels.

While antidepressants work for many people, a surprising number — some estimates put it at 50% or higher — are unresponsive. Furthermore, long term use of SSRI’s can have the effect of downregulating serotonin (5-HT2A) receptors with adverse results:

Another adaptive process provoked by SSRIs is the downregulation of postsynaptic serotonin 5-HT2A receptors. After the use of an SSRI, since there is more serotonin available, the response is to decrease the number of postsynaptic receptors over time and in the long run, this modifies the serotonin/receptor ratio. This downregulation of 5-HT2A occurs when the antidepressant effects of SSRIs become apparent. Also, deceased suicidal and otherwise depressed patients have had more [presynaptic] 5-HT2A receptors than normal patients. These considerations suggest that 5-HT2A overactivity is involved in the pathogenesis of depression

The last sentence in the above quote again points to the fact that a deficiency of post-synaptic serotonin receptors, in combination with  an excess of serotonin from diet, antidepressants, or elsewhere,  may play a role in both the genesis and worsening of depression.  The same phenomenon of receptor downregulation together with excess neurotransmitter has been noted with other antidepressants, such as MAO inhibitors and buproprion, that stimulate the production or prolong the lifetime of dopamine in the synapse.  This can lead to tolerance and withdrawal effects.

In short, in all these cases — obesity, addiction, and depression — receptors are becoming less sensitive to a signaling compound as a reaction to excessive levels of that compound.  So too much insulin and leptin lead to insulin and leptin resistance, too much dopamine to a downregulation of dopamine receptors.

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HOW TO UPREGULATE YOUR RECEPTORS. So if directly changing the amount of signaling compounds is frequently frustrated by receptor downregulation, is there anything you can do to upregulate the receptors?  Fortunately, the answer is yes.  There are a number of measures that have proven particularly effective for deliberately increasing the number and sensitivity of key classes of receptors:

Step 1:  Strenuous exercise. Regular, intense exercise can upregulate your insulin receptors. In Dr. Bernstein’s Diet Solution, Richard Bernstein explains the role of exercise in actually reversing insulin resistance by growing new muscle tissue, and by increasing the density of glucose transporter receptors in muscle and other tissues.  While his advice is directed primarily towards diabetics, it applies more broadly to anyone with some degree of insulin resistance That includes most of us.  According to Dr. Bernstein:

The higher your ratio of abdominal fat to muscle mass, the more insulin-resistant you’re likely to be. As you increase your muscle mass, your insulin needs will be reduced…Long-term, regular strenuous exercise also reduces insulin resistance independently of its effect upon muscle mass…In my experience, it takes about two weeks of daily strenuous exercise to bring about a steady, increased level of insulin sensitivity…via increased production of glucose transporters in muscle cells. (DBDS, p. 170-1).

Furthermore, the exercise must be strenuous and “anaerobic” – not aerobic.  There are two reasons for this:

First, the blood sugar drop during and after continuous anaerobic exercise will be much greater than after a similar period of aerobic exercise. Second, to accomplish efficient transport of glucose into muscle cells, as muscle strength and bulk develop, glucose transporters in these cells will greatly increase in number. Glucose transporters also become more numerous in tissues other than muscle, including the liver.  (DBDS, p. 180)

Glucose transporter (GLUT4) receptors are upregulated by intense exercise.  A study reported in the New England Journal of Medicine showed that this upregulation begins to happen within hours, but significant and sustained improvement requires repeated exercise sessions over several weeks.  When insulin levels are kept low, the glucose transporters migrate from a location inside the cell to protrude beyond the cell surface, becoming more available to bind glucose and shepherd it into the interior of the cell.  With time, the cells can actally express or “grow” additional receptors, increasing the overall rate of glucose transport.  This increased response rate is synonymous with “insulin sensitivity”.

The benefits of anerobic exercise extend not only to upgregulation of insulin receptors, but also to maintaining high levels of dopamine “reward” receptors. A study of exercised rates by McRae et al at University of Texas showed that regular exercise has a protective effect on D2 dopamine receptors, while keeping levels of dopamine (DA) and dopamine metabolite (DOPAC) low.  Unexercised rats saw both a decrease in D2 receptor density and an increase in circulating dopamine.

Step 2:  Calorie restriction and intermittent fasting. Another brain scan study at Brookhaven National Laboratory showed that restricted eating led to higher numbers of dopamine receptors in obese rats:

The scientists found that genetically obese rats had lower levels of dopamine D2 receptors than lean rats. They also demonstrated that restricting food intake can significantly increase the number of D2 receptors, partially attenuating a normal decline associated with aging.

This research corroborates brain-imaging studies conducted at Brookhaven that found decreased levels of dopamine D2 receptors in obese people compared with normal-weight people,” said Brookhaven neuroscientist Panayotis (Peter) Thanos, lead author of the current study, which will be published online in the journal Synapse on Thursday, October 25, 2007.

One of the essential points to understand here is that if calorie restriction and intermittent fasting are effective, it is not for the reason that most people think explains this (that you are creating a calorie deficit).  Rather, intense exercise and fasting work because they resensitize and grow your insulin and dopamine receptors in a way that allows you to get enough energy and pleasure from eating less food.   This means that not only are the receptors upregulated, but you also get the energy and pleasure when you need it.  So restricting calories is not good enough.  You must eat foods that maximize insulin senstivity (e.g. containing adequate essential fatty acids, protein, magnesium, etc.) and foods which give you enough pleasure so as to satisfy your “pleasure budget”, but not so much as to downregulate your dopamine receptors.  My experience is that intermittent fasting, using a varied diet, is the best way to do this.  One reason that pure “starvation diets” like that used in the Minnesota Starvation Experiment may have failed is that the diet failed to supply adequate nutrients that to support receptor function for cellular energy and pleasure.  (The 1560 calorie/day regimen consisted only of potatoes,  rutabagas,  turnips,  bread and macaroni — so go figure!)

A particularly effective protocol for improving insulin sensitivity and upregulating glucose transporter receptors is called “fasted workouts”: a combination of intense exercise and intermittent fasting, in which eating is postponed until after one works out.  One of the foremost practioners of this approach is Martin Berkhan, who I’ve referenced on the Fitness page of this blog, and whose Leangains blog I’ve listed under the Diet links.  Martin summarizes the research by DeBock et al. and Cluberton et al. that documents the physiological beneifts of fasted workouts, including enhanced insulin sensitivity based upon a six-week study with four 60-90 minute workouts per week. The study controlled for dietary intake, and compared results of those who fasted (F) with the control group (C) that ate prior to working out. Among other variables, the study compared changes in the levels of the GLUT4 transporter, a type of insulin receptor in the muscles, between the F and C groups:

Glucose transporter type 4 is a protein responsible for insulin-regulated glucose transport into the muscle cell. It increased by a whopping 28% in F but only 2-3% in C (not mentioned in the paper but this is my estimate based on the graphs). This partly explains why F saw superior results in regards to glucose tolerance and insulin sensitivity. Since GLUT4 is triggered by AMPK, which is increased when glucose availability is low, i.e. during fasted training, one would assume the GLUT4 increase could then be explained by an increase in AMPK. This was found to be true: AMPK increased by 25% in F, which correlated closely with the increase in GLUT4 content.

Step 3: Deconditioning and extinction. Pleasure reward circuits do not change overnight.  But the good news is that there is plenty of evidence that these reward circuits can be extinguished by classical conditioning techniques.  I’ve discussed these deconditioning techniques in depth on the Psychology and Diet pages of this blog, and I’d recommend looking there for details.  Extinction involves merely refraining from the undesired behavior (eating, addictive drugs) and allowing the cravings to happen without reinforcing them.  It may surprise you how quickly your reward circuits recover, and it is very likely that this involves upregulation of dopamine receptors, so that the brain is more easily “satisifed” without the previously craved behavior. Deconditioning is more active than extinction; it requires actively exposing yourself to cues which normally set off the addictive response.  This may sound extremely difficult, but is attested to by extensive research, as well as the personal experience of several people who have posted here on the Forum, including myself.   One of the more successful appliations of active deconditioning is the Sinclair Method, which has been used successfully to extinguish alcoholism while training the former alcoholic to drink moderately. The key is the use of a dopamine blocker, naltrexone, to block the reward circuits during exposure.

Any type of extinction should benefit from simultaneous reinforcement of healthy alternative sources of pleasure, while engaging in exercise and intermittent fasting to rebuild the density and sensitivity of receptors.  Unless you increase your level of dopamine receptors, you’ll always be vulnerable to the temptation of any pleasure that can “fill your pleasure deficit”.

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THE RECEPTOR CONTROL THEORY. Based upon a synthesis of extensive evidence, I’m putting forward in this post an alternative to the classic set point theory of Gordon Kennedy:  the receptor control theory.  This is a general hypothesis of biological regulation which applies to more than just weight control; it applies to any homeostatic variable that is controlled by cellular receptors — even, for example, pleasure and motivation. Whereas the classic set point theory of body weight posits a fixed genetic set point for each individual,

the receptor control theory postulates that our set points for regulating weight, energy, or pleasure are variable; they are directly related to the number, sensitivity and location of cellular receptors in our bodies, and can be modified by changing the number and sensitivity of these receptors.

For example, the set point for your body fat is controlled by insulin and leptin sensitivity, which is determined by the number and functional sensitivity of insulin and leptin receptors throughout your body.  As the number and sensitivity of insulin and leptin receptors decreases, body weight set point goes up. But unlike the set point theory, body fat set point can also go down by increasing the number and sensitivity of these receptors — for example by the use of strenuous exercise, intermittent fasting, and extinction.

If you don’t change the number and sensitivity of your receptors, your set point will not change.  Under these circumstances, the receptor control theory agrees with the classic fixed set point theory. However, the receptor control theory provides a way to change your set point by upregulating your receptors.

The pleasure budget. The receptor control theory goes beyond weight management to explain more generally the regulation of pleasure in your life.  If you have ample dopamine receptors, then a wide variety of stimuli– including food, social interactions, work, and other interests– should provide you with sufficient pleasure to make life not just bearable, but interesting.  However, if you end up with an undersupply of dopamine receptors — whether it be from birth, addictions or unremitting stress — then your baseline pleasure “set point” will be low and you’ll be vulnerable to depression, low self-esteem and other aspects of unhappiness. Addictive escapes may provide temporary (but unsustainable) bursts of dopamine, serotonin, and other feel-good neurotransmitters, but at the cost of further downregulating dopamine receptors and feeling worse later on.

It may be the case that all of us have a certain “pleasure budget” — perhaps we need a certain amount of pleasure every week, and we’ll find a way to get it, one way or another.  One of the commenters (zdd) to my earlier post on The opponent-process theory of emotion expressed this point well, when speculating about why diets like Shangri-La and Atkins work so well initially, but eventually become less effective:

If there is a set point, I believe it’s not a weight set point but rather a pleasure set point. When you don’t reach the set point, cravings start and when you go over the set point (staying too long at the fair) you get feelings of aversion.

I doubt if the pleasure set point changes very much. People simply switch sources of pleasure. Stop smoking, and you start eating more. Much of the pleasure of being on this diet comes from the pleasure of feeling in control. Once the novelty of control wears off people will have to look for other sources of pleasure or they will go back to getting pleasure from food.

I think this insightful comments carries a useful warning: that behavioral changes such as diets which cut off one source of pleasure may require us to find a way to replace that source of pleasure, or else risk rebounding from the diet and regaining the weight we lost.

The good news here is that there are proven ways to raise our “pleasure” set point.  The bad news is that they require significant and sustained effort – no quick fixes.  And yet it is the most sustainable way to increase pleasure in life.  To paraphrase a saying about fishing sometimes attributed to the Bible: “Give someone a neurotransmitter and they’ll feel good for an hour; teach someone to grow more receptors and they’ll feel good all the time.”

Explanations. The receptor control theory explains a number of observations that cannot be accounted for by classical set point theory:

1. Biology is not destiny. Individuals do differ genetically in their tendency to gain weight or to be prone to addiction or depression.  You are born with a certain density of receptors and this can be influenced further during prenatal and postnatal development.  But it is not the end of the story. The types of foods you eat and the frequency of eating have strong effects on insulin and leptin sensitivity.  Likewise, exercise, hard work and a stoic practices can sensitize your dopamine receptors and make you happier and less prone to depression.
2. Obesity is not a constant. Both the weight gain of individuals as they age, and the obesity epidemic of recent decades are often blamed on “calorie imbalance”: eating too much and exercising too little. But this doesn’t explain why this caloric imbalance is happening now as opposed to earlier. Sometimes the uptick in obesity is blamed on the increasing availability of tasty high-calorie food and a less active lifestyle. But that explanation cannot be right, because there has always been tasty food. And as Kolata has shown, controlled interventions to reduce calories and enforce more activity have a poor track record.  The reason that body weight set points are rising has more to do with changes in the amounts of food and exercise, as it does with specific types of food, eating patterns and exercise–and the long term hormonal influences of these changes on receptor sensitivity.
3. Permanent weight loss is still possible. Granted, most diets don’t work. Quick weight loss diets don’t work because they don’t allow a biologically realistic amount of time for receptors to upregulate; receptor upregulation is a gradual process that requires persistence and effort. Certain diets are quite effective in the short term, including low carbohydrate diets, low glycemic diets, and the Shangri-La Diet (which temporarily suppresses appetite). These diets will temporarily change levels of hormones, neurotransmitters and other signalling compounds to induce satiety and weight loss. However, unless appetite circuits are permanently “re-wired” by upregulating hormonal and neural receptors, weight loss will be temporary.  Appetite will remain vulnerable to coming back like a tiger, and you may return to your old set point weight — perhaps even plus a few pounds.  The best way to upregulate metabolic and appetite receptors is by strenuous exercise, intermittent fasting or deconditioning.  Given enough time, persistent and habitual dietary changes can lead to permanent weight loss, particularly when combined with reduced eating frequency, intense exercise, and deconditioning.

Biological basis for Hormetism. The receptor control theory also provides us with a some biological underpinnings for Hormetism and Stoicism, as advocated in this blog. Hard work –tough, uncomfortable and challenging activities–can lower our metabolic and pleasure set points, helping us to lose weight and making us less vulnerable to addictions, cravings and depression.  What is exciting to me is that this theory may provide a possible biological basis for the psychological Opponent-Process Theory of Richard Solomon.  The basis is located not in transient chemical messengers like neurotransmitter and hormones, but rather in the adpatable receptors located throughout our body on every cell.  These receptors are part of the hardware or firmware of our bodies and brains.   Receptors are a part of us that cannot be changed overnight, but can only be changed with persistent effort.  (And they will not disappear so readily either).

I will be the first to acknowledge that at this point the receptor control theory is just that — a theory.  It has support by scientific evidence, but many questions remain.  And yet it is a productive theory which generates many testable hypotheses.  It provides us with a possible basis for understanding the benefits of less-studied hormetic or Stoic practices such as showering or swimming in cold water, radiation hormesis, or allergen immunotherapy.  Do these types of stress also result in upregulation or downregulation of specific cellular receptors involved in pain perception, cellular repair, inflammation or immune response? Can we measure and better understand these responses at the level of receptors? Are there practical ways to measure the number and sensitivity of our receptors, so that we can track progress? Receptor change is probably only one of many mechanisms that explain hormesis, but it may be an important and underappreciated one.  These questions make good topics for future posts.

Finally, unlike the classic set point theory, the receptor control theory is not fatalistic, but is optimistic:  By combining insights as old as ancient Stoic philosophy with a contemporary scientific understanding of psychological conditioning and the plasticity of cellular signal receptors and receptor circuits, we can work to achieve fitness and weight loss, freedom from addictive compulsions, and chart other major changes in our metabolic and psychological well being.