How Hormesis Works

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Posted 19 Jul 2018 in Uncategorized

I had the pleasure of delivering a presentation on this topic today at the Ancestral Health Symposium, in beautiful Bozeman, Montana.  This is my fourth such talk at AHS, a non-profit educational organization which brings together a collection of academics, practitioners, bloggers and others interested in evolutionary mismatch and its implications for health and well-being.

I’m posting the slides from my talk here – click on the image to see a pdf.  I’ll upload the full video once it becomes available in a few weeks.




This talk is about the biological mechanisms that explain hormesis – the beneficial  adaptation  to  intermittent, low dose stress.  Here is a synopsis of the talk, slide by slide:

  1. Title: How Hormesis Works: The Biology of Beneficial Adaptation to Stress
  2. The Getting Stronger blog has many specific examples of hormesis.  I have spoken at AHS on 3 prior occasions on different topics, but this will be a deeper dive into the mechanisms that underlie all types of hormesis.
  3. We are faced with pandemics of metabolic disease and psychological disorders.  Do these result from too much stress, or perhaps too little beneficial stress?
  4. Hormesis is defined as the beneficial response  of an organism to a low dose stressor that is otherwise detrimental or lethal at higher doses.
  5. A survey of 9000 toxicology dose response curves in microbes, plants and animals show that 19.5% of them display evidence of a positive or stimulatory effect at lower doses.  The hormetic concentrations vary considerably for different chemicals, stressors and organisms.
  6. Why does hormesis exist?  Organisms must be able to adapt to changing, stressful environments or face extinction.
  7. Ancient man was a hunter gatherer, often facing food shortages, lack of shelter and infection.  Our modern evolutionary mismatch may be the fact that we are too comfortable and protected from the hormetic stimuli in our natural environment.
  8. But how does hormesis actually work?  What are the underlying biological mechanisms?
  9. I propose a “Hormetic Hierachy” of four main types of hormesis.  Starting at the foundation and moving higher, these types are: structural, defense, metabolic and psychological.
  10. STRUCTURAL HORMESIS is the strengthening or adaptation of structural tissues in response to mechanical stimuli such as pressure, friction or stretching.
  11. Resistance  exercise for muscle growth is the classic example of structural hormesis.  Straining causes micro-trauma, release of growth factors that cause satellite cells to fuse into existing muscle and increase size and strength.
  12. This results in supercompensation.  Immediately after training, there is a decrease in strength or fitness.  After rest and recocvery, the resulting strength or fitness exceeds baseline.
  13. Bone is also strengthened by exercise  that  involves loading. This stimulates integrin proteins in the osteocyles to release FAK, leading osteoblasts to migrate, secrete collagen, and mineralize.
  14. Callus forms on skin in response to friction that stimulates the crosslinking of protein and keratinocytes by transglutaminase.
  15. Myopia is also a result of structural changes in the eye.
  16. Excessive reading or screen time induces pseudomyopia (spasm in the lens) resulting in blurry distance vision .  Getting minus lenses for distance correction temporarily solves the problem, but the eye is induced to elongate, cause, spurring a repeated need for stronger lenses.
  17. The lengthening of the eye axis results when repeated cycles of retinal defocus slow the release of neuromodulators that control proteoglycan synthesis in the sclera.  This weakens the scleral tissue integrity, increasing the eye’s axial length. Hyperopia is the opposite process.
  18. This explanation is supported by research in animals and humans showing how minus lenses begin lengthening the eye, while plus lenses shorten. This process starts in less than an  hour after wearing these lenses.  Repeating cycles consolidates the change.
  19. Myopia can thus be reversed by wearing plus lenses and print pushing while reading or at computers, and using progressively weaker minus lenses for distance viewing.
  20. DEFENSE HORMESIS is the strengthening of immune  and xenobiotic defenses against foreign substances  and organisms, by appropriate exposures.
  21. The dramatic rise of allergy and autoimmune disease may be associated with the loss of our “ancestral microbiome” — a set of commensal organisms that co-evolved with us to stimulate regulatory T-cells which  moderate our B and T immunes cells not to over-react.
  22. The book “An Epidemic of Absence” by Velasquez-Manoff details numerous examples of allergies and  autoimmune  diseases controlled by exposure to microbes at specific life stages, including asthma, celiac, multiple sclerosis and autism.
  23. Xenobiotic metabolism is our defense against chemical toxins, including the natural plant toxins that we call “phytonutrients”.  The Nrf2 transcription factor mediates the production of endogenous Phase II antioxidant enzymes that neutralize oxidative stress from toxins as well as exercise.  Ironically, taking oral antioxidants suppresses Nrf2 and counteracts exercise benefits.
  24. METABOLIC HORMESIS is the improved capacity and flexibility to utilize dietary or stored energy.
  25. Hormesis activates a powerful “stress sensor” called PGC-1α, that triggers wide-ranging metabolic changes, starting with mitochondrial biogenesis.  PGC-1α is triggered by stressors such as cold exposure, exercise,, calorie restriction and hypoxia.  A train of hormonal and enzymatic changes bring about appetite suppression, exercise urge, insulin sensitivity and autophagy.
  26. PGC-1α inhibits mTOR activity, the master regulator of protein synthesis and growth processes.  While important in childhood and adolescent development, mTOR is associated with metabolic diseases of aging.  PGC-1α induces the protein REDD-1 that inhibits mTOR.
  27. PGC-1α also spurs autophagy, a cellular housecleaning process that digests damaged intracellular proteins and other byproducts.
  28. Autophagy promotes longevity by reducing inflammation, apoptosis, senescence and oncogenesis.  It stimulates the innate immune response  and removes intracellular pathogens.
  29. A popular theory of why we age is that we accrue progressive oxidative damage, impairing cellular function.
  30. The long-lived naked mole rat is a counterexample to the accumulated damage theory.  It is wracked with extensive oxidative damage in the skin and organs, yet lives 30 years compared to 3 years for laboratory mice.  It protects against the results of this damage via endogenous antioxidant enzymes.
  31. PGC-1α upregulates BDNF, which induces neurogenesis in the brain and improves insulin sensitivity in the muscles.
  32. The PGC-1α cascade also induces exercise salience — the urge to exercise.
  33. In the virtuous circle of hormesis, PGC-1α turns on mitochondrial biogenesis, improving energy flow, increasing the urge to exercise and suppressing appetite and inflammation.  This leads us to be more resilience and willing to expose ourselves to further hormetic stressors.
  34. In  the viscious cycle of inflammation, a sedentary lifestyle, caloric excess and inflammatory foods suppress mitochondrial biogenesis, lowering energy level and increasing the urge to eat while suppressing the desire to exercise.
  35. Keto-adaptation is another example of metabolic hormesis.  While it takes only a few days of fasting to induce ketosis, true keto-adaptation takes several weeks.  A great reference for these metabolic changes is  Phinny and Volek’s “The Art and Science of Low Carbohydrate Performance”, and their website
  36. PSYCHOLOGICAL HORMESIS is increased resilience in the face of discomfort, by voluntary exposure to challenges.
  37. The opponent-process theory of emotion was developed to explain hedonic reversal: how, with time, pleasures become increasingly addictive, while certain uncomfortable challenges become tolerated and even lead to sustained pleasure after the event.
  38. The classic example studied by Solomon and Corbit was skydivers.  While the first jump provokes terror and some satisfaction after the jump is complete, after many jumps the initial fear experience is diminished, while the post-jump experience becomes euphoric and sustained.
  39. This phenomenon is explained by an inhibitory or opponent “B” process that counteracts the intensity of either the pleasure or pain of the intense “A” process. The B process becomes stronger with repetition, dampening the initial intensity of A and sustaining and deepening the intensity of B.
  40. These compensating opponent processes are not “mere psychology”, they are matched by underlying neurological changes. One example is the down-regulation of D2 dopamine receptors, imaged in PET brain scans, as seen in a study of smokers, alcoholics, cocaine users and the obese.
  41. Dopamine receptors are significantly down-regulated in cocaine over 6-12 months, deepening addictive cravings.
  42. Conversely, dopamine receptors can be upregulated hormetically.  Lean rats start with higher receptor density than obese rats, but both show dramatic D2 receptor activity increase after 4 months of caloric restriction.  Similar trends are seen in methamphetamine users who exercise while abstaining.
  43. SSRI anti-depressants exhibit tolerance associated with down-regulation of serotonin receptors.  But exercise has been show to have a lasting anti-depressant effect.
  44. I propose a “receptor control theory”, in which individuals have “pleasure set points” determined by the  number and sensitivity of different types of receptors.  Hormetic activities can increase receptor density, and thereby improve well-being and resilience to stress.
  45. GENERAL PRINCIPLES of hormesis at all 4 levels include: plasticity, specificity,  supercompensation, secondary adaptation, and intermittency.
  46. Secondary adaptation involving lasting changes typically takes weeks or months to consolidate.
  47. Stress oscillation is important.  Hormetic stress exposure should alternate with periods of rest to enable consolidation and avoid chronic stress and burnout.
  48. In summary, hormetic challenge at all levels can bring about increased performance, health and resilience. Try out some hormetic activities like intermittent fasting, cold showers, rock climbing or sky diving!

Slide 49-52 provide supporting references.

I’d also recommend scanning through past articles posted on this blog for more detail on specific examples of hormesis.



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