Hormesis – What doesn’t kill you, makes you stronger.

If a little of something is good for you, more is not necessarily better, and might be worse.

 Smoking more than ten modern tobacco cigarettes daily is the single biggest risk factor for progressive periodontal disease as well as the stressed metabolism of syndrome X which includes diabetes, arthritis, depression, heart and artery disease, stroke and cancer. 

 Even low levels of secondhand smoke are harmful to some populations (especially developing children and the elderly).  Most modern tobacco is sugar-cured, so habit-forming nicotine is now synergized with the alluring addictive taste of inhaled caramelized sugar while we seek our primitively programmed oral suckling rewards. 

 Diabetes is by itself the second biggest risk factor for modern society’s primary killer diseases.  Diabetes is controlled by eliminating addictive foods with high glycemic load such as boxed breakfast cereals, breads, cakes, pancakes, waffles, pop-tarts, donuts, cookies, pretzels, French fries and chips of all varieties. 

 Like modern corporatized tobacco, these favorite foods that trigger high blood sugar responses also feature the tempting taste of caramelized sugar.  Repeated high blood sugar response to these heated and deformed food molecules creates a stressed metabolism with loss of homeostatic controls while enhancing enzymatic caramelization and stiffening of our own tissues.

 Toasted sugars become browned and rigidly shaped when glycated by heat.  When our own tissues stiffen and harden enzymatically due to high availability of sugar, it is called glycosylation.  In industry these AGEs (advanced glycation end-products) are also called acrylamides or polyacrylamides and they are well known carcinogens. 

 Collecting increased AGEs in one’s body causes cataracts, wrinkles and age spots in the skin as well as the rigidity, brittleness and neuropathy of old age.  AGEs mimic heat shock protein in our bodies, mimicking stress messenger-molecules created in response to burns or bacterial infection.

 If AGEs are so bad for us, why do we love the taste of caramel so much? The controlled caramelization of the sugars, starches and proteins in foods creating pleasing flavor nuances is the basis of most modern cooking.  Surprisingly, a little bit of such food derived stress is good for us, making us stronger and able to handle bigger strains.  It is just too cheap and easy for modern man to toast things, thus we too frequently send these tasty but overwhelming biochemical stress-signals of ‘forest fire’ to our primitive genes.

  The challenging and controversial concept that poisons can heal when given in low doses is explored in “Sipping from a Poisoned Chalice” (Science - Oct 17, 2003, Vol. 302).  Organisms can respond with a great variety of responses after exposure to a stimulus or chemical, be it beneficial, adaptive, or early manifestations on a range to toxicity, overt toxicity as well as several of these in combination.  For ages, a small minority of people (mostly homeopaths) have also known through ‘provings’ that small doses of poisons can paradoxically produce beneficial effects.

 Usually one expects a graded linear response to a stimulus from low to medium to high.   Hormesis describes the unexpected finding that in an organism, often a specific stressor or chemical is able to induce biologically opposite effects at different doses; often there is a stimulatory or beneficial effect at very low doses and an inhibitory or toxic effect at higher doses. 

 The wide range of hormetic effects (stress resistance, altered metabolism with increased growth, fecundity, genetic stability and longevity, immune-regulation as well as decreased disease incidence) indicates that these changes are fundamental endurance responses of the organism that affect thousands of genes.  Although there is no single specific hormetic pathway, there seems to be a common biological continued existence strategy underlying such beneficial observations.

 Hormesis defines the capacity of a chemical or physical agent to condition the physiological state of an organism to tolerate higher stress with very low doses of otherwise harmful agents.  Evolutionary evidence demonstrates that the continued existence and longevity of species hinge on their optimal ability to resist stress challenge.  Hormesis is a potent survival strategy to stimulate latent repair processes to enhance overall tolerance to challenge.

It is common wisdom that an infant benefits from earlier rather than later exposure to the world at large and that without such challenges is unlikely to cope as well with sudden delayed exposure.  This hormetic principle extends into adulthood and fades with senescence.

 Brief whole-body exposure to cold water increases both activity and numbers of peripheral natural killer (NK) cells and CD8+ T lymphocytes.  Likely transient activation of the sympathetic nervous system, the hypothalamic-pituitary-adrenal axis as well as the hypothalamic-pituitary-thyroid axis results in a brief action of norepinephrine, adrenocorticotropic hormone (ACTH), beta-endorphin as well as thyroid hormones {triiodothyronine (T3) and thyroxine (T4)} on cytotoxic T lymphocytes and NK cells. 

 Cold water stress enhances survival with its analgesic effect and by encouraging cellular immunity while reducing tumor formation and autoimmunity.

 A wide variety of physical, chemical and biological agents exhibit hormetic effects, including heavy metals, pesticides, antibiotics, chemotherapeutic agents, vitamins, hormones and hormone mimics like plasticizers, ethanol, aldehydes, chloroform, pro-oxidants, hypergravity and ionizing radiation.

 Glucose and oxidation-mediated protein and DNA damage are common underlying causes of many age-related diseases.  Physiological hormetic conditioning may trigger:  1) activation of latent stress resistance pathways of youthful DNA repair;  2) increased resistance to oxidizing pollutants;  3) improved protein structure and function;  4) improved immunity;  5) damaged tissue remodeling;  6) adjustments in central and peripheral nervous systems;  7) altered metabolism; and 8) delay or breaking of inappropriate protein cross-links.

 The hormetic dose–response challenges long-standing beliefs about the nature of the dose–response in a low dose zone and has the potential to affect significantly the design of pre-clinical studies and clinical trials as well as strategies for optimal patient dosing in the treatment of numerous diseases.

 Hormetic messengers or mimetics may help prevent cancer, diabetes, age-related diseases, infectious diseases, heart and kidney failure, cardiovascular diseases and Alzheimer’s disease.  Small nucleotide SOS signals, dipeptides, ethanol, thiols and metals as well as conserved peptide sequences found in sharks, frogs, woodchucks and bears, can regulate cytokines, cellular immunity as well as central and peripheral neuronal regulatory pathways to promote healthy blood pressure maintenance, heart rate and metabolic pathways, reducing disease sensitivity.

 Stress mimetics rejuvenate DNA as well as enhance repair of proteins and thus may intervene in aging, disease and trauma.  Deltorphins (stress-induced hibernation-induction trigger mimetics which fit delta endorphin receptors), come to light as new hormetic agents, effective both as pre and post exposure to physiological conditioners to tolerate trauma as well as prevent damage, and possibly delay aging.  

Botulinum

Botulinum is one of the most poisonous substances known.  A gram of botulinum toxin, if dispersed and ingested could kill 20 million people.   Yet, Botox treatment to remove wrinkles is botulinum in extremely dilute form.

 

Other applications include relief of migraines, a cure for crossed eyes as well as a treatment for the spastic conditions of multiple sclerosis and cerebral palsy.  A combination of botulinum and a protein from the Mediterranean coral tree could provide a treatment for the chronic pain that afflicts millions of people, including cancer patients.  

Treatments with botulinum toxin can often help focal dystonia, a misfiring of the brain that causes muscles to contract into abnormal and sometimes painful positions.  This career threatening disorder often strikes those who depend on small motor skills: musicians, writers and surgeons.   

Hydrogen sulfide (H2S)

According to the OSHA fact sheet, hydrogen sulfide is a colorless, flammable, extremely hazardous gas with a “rotten egg” smell.  Hydrogen sulfide is heavier than air and may travel along the ground. It collects in low-lying and enclosed, poorly-ventilated areas.  Hydrogen sulfide is both an irritant and a chemical asphyxiant with effects on both oxygen utilization and the central nervous system.

 

Its health effects can vary depending on the level and duration of exposure. Repeated exposure can result in health effects occurring at levels that were previously tolerated without any effect.

 

Low concentrations irritate the eyes, nose, throat and respiratory system (e.g., burning/tearing of eyes, cough, shortness of breath).  Asthmatics may experience breathing difficulties.  The effects can be delayed for several hours, or sometimes several days, when working in low-level concentrations. Repeated or prolonged exposures may cause eye inflammation, headache, fatigue, irritability, insomnia, digestive disturbances and weight loss. 

 

Moderate concentrations can cause more severe eye and respiratory irritation (including coughing, difficulty breathing, and accumulation of fluid in the lungs), headache, dizziness, nausea, vomiting, staggering and excitability.

 

High concentrations can cause shock, convulsions, inability to breathe, extremely rapid unconsciousness, coma and death. Effects can occur within a few breaths, and possibly a single breath.

 Hydrogen sulfide is considered a broad-spectrum poison, meaning that it can poison several different systems in the body, although the nervous system is most affected. The toxicity of H2S is comparable with that of hydrogen cyanide. It forms a complex bond with iron in the mitochondrial cytochrome enzymes, thereby blocking oxygen from binding and stopping cellular respiration.

 Since hydrogen sulfide occurs naturally in the environment and the gut, enzymes exist in the body capable of detoxifying it by oxidation to (harmless) sulfate.  Hence, low levels of sulfide may be tolerated indefinitely.   However, at some threshold level, the oxidative enzymes will be overwhelmed.

Hydrogen sulfide is produced in small amounts by some cells in mammals and has a number of biological functions.  It is enzymatically produced from cysteine.  It acts as a vasodilator and is also active in the central nervous system, where it increases the response of the NMDA receptor and facilitates memory.

 

Eventually the gas is converted to sulfites and further oxidized to thiosulfate and sulfate.   Due to its effects similar to NO (without its potential to form free radicals by interacting with superoxide), hydrogen sulfide is now recognized as a potential cardioprotective agent.  Vasoactivity of garlic is partly caused by catabolism of the polysulfide group in allicin to H2S, a reaction which likely depends on reduction mediated by glutathione (which the other parts of garlic help recycle).

 

 Hydrogen sulfide binds to cytochrome oxidase and thereby prevents oxygen from binding, which leads to the dramatic slowdown of metabolism.  Animals and humans naturally produce some hydrogen sulfide in their body, perhaps to regulate metabolic activity and body temperature.

 

 Mice can be put into a state of suspended animation like hypothermia by applying a low dosage of hydrogen sulfide (81 ppm H2S) in the air, roughly the amount that will cause eye damage to humans at work.  If the H2S-induced hibernation can be made to work in humans, it could be useful in the emergency management of severely injured patients and in the conservation of donated organs.

 

 Several interrelated cellular signaling molecules are involved in the process of hormesis.  Examples include the gases oxygen, carbon monoxide and nitric oxide, the neurotransmitter glutamate, the calcium ion and tumor necrosis factor.

 In each case low levels of these signaling molecules are beneficial and protect against disease, whereas high levels can cause the dysfunction and/or death of cells.  Hormesis conditioning offers powerful survival strategies.  Combinations of several mimetics may more closely imitate environmental challenges.

Oxygen

 Hormesis may be induced by endogenously produced, potentially toxic agents.  For example, mitochondria consume oxygen which generates free radicals (reactive oxygen species) as an inevitable by-product.

The biochemical basis for the toxicity of oxygen is the partial reduction of oxygen by one or two electrons to form reactive oxygen species, which are natural by-products of the normal metabolism of oxygen and have important roles in cell signaling.   One species produced by the body, the superoxide anion (O2), is likely involved in iron acquisition.

 The superoxide radical serves as both an initiator and a terminator of the free radical-mediated chain reaction resulting in lipid peroxidation.  Lipid peroxidation is a universal feature of oxidative stress, causing loss of cellular structure and function.  Under any given conditions, the optimal concentration of SOD is that which decreases chain initiation without elimination of the chain termination properties of the radical, resulting in a minimum of net lipid peroxidation.

 Higher than normal concentrations of oxygen lead to increased levels of reactive oxygen species. Oxygen is necessary for cell metabolism, and the blood supplies it to all parts of the body.  When oxygen is breathed at high partial pressures, a hyperoxic condition will rapidly spread, with the most vascularized tissues being most vulnerable.  During times of environmental stress, levels of reactive oxygen species can increase dramatically, which can damage cell structures and produce oxidative stress.

 While all the reaction mechanisms of these species within the body are not yet fully understood, one of the most reactive products of oxidative stress is the hydroxyl radical (·OH), which can initiate a damaging chain reaction of lipid peroxidation of the unsaturated lipids within cell membranes. 

  High concentrations of oxygen also increase the formation of other free radicals, such as nitric oxide, peroxynitrite and trioxidane, which harm DNA and other biomolecules.   Although the body has many antioxidant systems such as glutathione that guard against oxidative stress, these systems are eventually overwhelmed at very high concentrations of free oxygen, and the rate of cell damage exceeds the capacity of the systems that prevent or repair it.   Cell damage and cell death can then result.

 Free radicals may induce an endogenous response cumulating in increased defense capacity against exogenous radicals (and possibly other toxic compounds).  Indeed, such induction of endogenous free radical production through exercise extends life span of a model organism.  Interestingly, this induction of life span is prevented by antioxidants, providing direct evidence those toxic radicals may hormetically influence the mitochondria and exert life extending and health promoting effects.

 Since mitochondrial activity was found to be increased in the before-mentioned studies, this effect cannot be explained by an excess of free radicals that might mark mitochondria for destruction by lysosomes, and that the free radicals act as an apoptotic signal within the cell indicating which mitochondria are ready for destruction.

Carbon Monoxide

 Carbon monoxide is an example of a ‘pollutant’ that is important for human existence.  This deadly gas that kills thousands each year offers potential help for a number of medical conditions.

 There are pathogenic implications for conditions that substantially raise the tissue CO content and produce oxidative stress, such as smoking, air pollution and CO poisoning as well as hemolytic or inflammatory states that accelerate heme turnover.  Although carbon monoxide inhalation can be lethal, our bodies make CO molecules naturally in small amounts when an enzyme called heme-oxygenase-1 (HO-1) breaks down a portion of the blood protein hemoglobin.  

 Ventilator-induced lung injury (VILI) is a major cause of morbidity and mortality in intensive care units. The stress-inducible gene product, HO-1 and carbon monoxide, a major by product of the oxygenase catalysis of heme, have been shown to confer potent anti-inflammatory effects in models of tissue and cellular injury.  Inhaled low-dose CO might be useful in minimizing VILI.

  Small amounts of carbon monoxide might alleviate symptoms of multiple sclerosis, a study in mice suggests. Other studies of laboratory animals suggest that carbon monoxide in small doses can prevent injury to blood vessels caused by surgery. In this study, rats that inhaled carbon monoxide-laced air for 1 hour before angioplasty had much less subsequent artery blockage than did rats not receiving the gas. Rats that underwent a vessel transplant also fared significantly better if given carbon monoxide before and after the surgery.

  Low concentrations of CO act very rapidly on the macrophage and induce stabilization of the transcription factor hypoxia inducible factor 1α (HIF1α), a potent oxidant stress response gene responsible for regulating gene expression involved in angiogenesis, metabolism and survival.  The ability of CO to increase HIF1α activity is mediated in part by a highly significant and transient burst of reactive oxygen species (ROS) arising from the mitochondria.

 CO-mediated HIF1α activity then leads to the induction and secretion of TGFβ, a potent anti-inflammatory cytokine.  The induction of both HIF1α and TGFβ by CO are necessary to rescue lung macrophages from anoxia/reoxygenation-induced apoptosis and ischemia-reperfusion injury.

 Modest increases in cellular CO concentration activate mitochondrial biogenesis.  Mitochondrial generation of reactive oxygen species by CO activates mitochondrial biogenesis in the heart.  Mitochondrial CO and H2O2 are activating factors in cardiac mitochondrial biogenesis.  Mitochondrial H2O2 production deriving from CO binding to cytochrome c oxidase is an activating factor in mitochondrial biogenesis.  

 Mitochondrial biogenesis is activated by gene and protein expression of the nuclear respiratory factor 1 (NRF1) and NRF2, of peroxisome proliferator-activated receptor gamma co-activator-1 , and of mitochondrial transcription factor A (TFAM), which augmented the copy number of mitochondrial DNA (mtDNA).  This is independently of nitric oxide synthase (eNOS and iNOS) or hypoxia.

Nitric oxide (NO)

 Nitric oxide is an air pollutant produced by cigarette smoke, automobile engines and power plants.  NO is also an important messenger molecule involved in many physiological and pathological processes within the mammalian body both beneficial and detrimental.  Appropriate levels of NO production are important in protecting an organ such as the liver from ischemic damage.

 However sustained levels of NO production result in direct tissue toxicity and contribute to the vascular collapse associated with septic shock, whereas chronic expression of NO is associated with various carcinomas and inflammatory conditions including juvenile diabetes, multiple sclerosis, arthritis and ulcerative colitis.

 The dilating mechanism is mediated by the formation of gaseous nitric oxide from nitrites.  Nitric oxide (NO) is a molecule used by the endothelial cells lining the surface of blood vessels to signal surrounding muscle to relax, leading to a reduction in blood pressure, reduced blood clotting and protection against myocardial infarction and strokes. 

 Coexpression of eNOS, VEGF (vascular endothelial growth factor) and angiopoietin-1 results in more mature vascularization of connective tissue, and generates new arterioles as well as new capillaries.   Combining hemodynamic forces with growth factors provides a more physiological therapeutic approach than single growth factor administration. 

 VEGF is part of a sub-family of cystine-knot growth factors including platelet-derived growth factor (PDGF) and placenta growth factor.  Cystine knots are the result of an unusual arrangement of six cysteine residues. 

 Cystine knot structures are found in nerve growth factor, tumor growth factor-beta, chorionic gonadotropin, luteinizing hormone, follicle stimulating hormone and thyrotrophin (thyroid stimulating hormone or TSH) also contain subunits with a cystine knot structure.  Sulfur-containing cysteine does much more than function as the rate-limiting amino acid for the formation of critical glutathione, so pivotally important for energy production and cellular immunity.

 VEGF production is induced in cells that are not receiving enough oxygen (as in anemia induced by nitrite-induced methemoglobin).  When a cell is deficient in oxygen, it produces HIF, hypoxia inducible factor, and a transcription factor which stimulates the release of VEGF, among other functions (including modulation of erythropoeisis).  Circulating VEGF then binds to VEGF receptors on endothelial cells, triggering a tyrosine kinase pathway leading to angiogenesis.

 Generation of contractile microvessels (arteriogenesis) is required for the development of therapeutic angiogenic strategies.  This can be achieved by combining vascular growth factors (VEGF and angiopoietin-1) with eNOS over expression, providing extra messaging for neovascular gene therapy.
 

 However, excessive production of NO can lead to efficiently feeding new tumors, macular degeneration, diabetic retinopathy, hypertrophy of kidney glomeruli allowing proteinuria or the production of toxic oxidizing peroxynitrites, causing arterial injury or neuropathy leading to ‘brain on fire’ expressed as cognitive dysfunction, Alzheimer’s or Parkinson’s disease.

 The formation of reactive nitrogen species is not the usual consequence of synthesizing NO.  NO is efficiently removed by reacting with circulating oxyhemoglobin to form nitrate, which prevents even the highest rates of NO synthesis from directly reacting with oxygen to form significant amounts of nitrogen dioxide. 

 However, the simultaneous activation of superoxide synthesis along with NO will completely transform the biological actions of NO by forming peroxynitrite.  Several enzyme complexes, such as NADPH oxidases (NADPHox) and xanthine oxidase (from pasteurized cow’s milk protein), can be activated in many cellular systems to actively produce large amounts of superoxide.

 What happens when superoxide and NO are produced simultaneously in close proximity? Modestly increasing superoxide and NO each at a 10-fold greater rate will increase peroxynitrite formation by 100-fold.  Under proinflammatory conditions, simultaneous production of superoxide and NO can be strongly activated to increase production 1,000-fold, which increases peroxynitrite formation by a 1,000,000-fold. 

 Without superoxide, the formation of nitrogen dioxide by the reaction of NO with oxygen is miniscule by comparison. However, NO and superoxide do not even have to be produced within the same cell to form peroxynitrite, because NO can so readily move through membranes and between cells.

  NO is mostly removed by reacting with oxyhemoglobin to form nitrate, with only a small fraction being oxidized by heme proteins.  NO is the one molecule produced in high enough concentrations and reacts fast enough to competitively react with endogenous SOD (superoxide dismutase) for superoxide.  Nitric oxide reacts rapidly with superoxide to form the potent free radical peroxynitrite. 

 Cells can be activated to produce large amounts of superoxide by specific NADPH oxidases and other enzymatic sources.  Because the rate of peroxynitrite formation rises 100-fold for each 10-fold increase in superoxide and NO production, the production of superoxide offers a dynamic mechanism to redirect NO from being a signaling molecule to an important component of host-defense and innate immunity.

 This primary peroxynitrite weapon of the immune system is usually tightly controlled within the peroxisomes of white blood cells.  Unbuffered peroxynitrites may produce a number of types of tissue damage, including free radical damage to the mitochondria (energy producing organelles within cells) and to cell membranes through oxidative chain reactions.  Adequate recycled reduced glutathione from precursors and fresh organic foods is the key to quickly quenching peroxynitrites.

 Extreme caution must be exercised in adding nitrate or nitrite to meat, since these ingredients tend to be toxic to humans.  In using these materials never use more than called for in the recipe.  A little is enough. 

 Potassium nitrate can cause gastroenteritis (violent stomach ache), low blood pressure, anemia, kidney disease as well as general weakness and torpor.  It also has an alarmingly depressive effect on the heart.  Potassium nitrate and other nitrates do successfully combat high blood pressure and are used medically to relieve angina and cold vasoconstrictive migraine.  Potassium nitrate is also used in dental cements and toothpastes to instantly desensitize hypersensitive teeth.

 Nitrates themselves are relatively nontoxic.  However, when swallowed, especially if one has low stomach acid, opportunistic bacteria convert nitrates to nitrites that can react with circulating hemoglobin, oxidizing its divalent iron to the trivalent form and creating methemoglobin. 

 

 Methemoglobin cannot bind oxygen, which decreases the capacity of the blood to transport oxygen so less oxygen is transported from lungs to body tissues, causing methemoglobinemia. 

 

 Normal individuals have low levels (0.5-2%) of methemoglobin in their blood.  When this level increases to 10%, the skin and lips can take on a bluish tinge (cyanosis) and levels above 25% can cause weakness and a rapid pulse.  At levels above 50-60%, a person can lose consciousness, go into a coma and die. 

 

 Infants are much more sensitive than adults to nitrates/nitrites.  Essentially all deaths from nitrate/nitrite poisoning have been in infants.  Long-term exposure to nitrates and nitrites can cause diuresis (an increase in the excretion of urine, and starchy deposits or hemorrhaging in the spleen).

 

 Nitrates are found naturally in spinach, eggplant, beets, green lettuce, turnip greens, green beans, carrots, radishes, celery and collards.  Most babies’ liver detoxification enzyme systems are well enough developed by 9 months of age to handle purees of these wonderful fiber-rich and nitrate-rich foods. 

 

 Nitrogen in chemical fertilizers oxidizes into nitrates that these plants absorb.  These nitrates cause part of the bitter flavor associated with some greens such as collards.  Organic vegetables contain significantly less nitrates because natural compost is used to fertilize the soil. 

 

 Organic vegetables are also richer in polyphenols, antioxidants, vitamins and minerals.  Nitrate fears should not be used as an excuse to avoid them, since their fibers safely sequester nitrites.  It is, however, one more reason to vote ‘organic’ with your food-purchasing dollar.

Homeopathy and Water

 Hormesis validates homeopathy, which is controversial (mostly to conventional medical doctors whose minds have been brutally trained to think only linearly).  The homeopathic therapeutic concept believes that extremely diluted toxicants can be beneficial to human health, relieving similar symptoms generated by larger doses.  Hormesis is truly a real biological phenomenon, supporting the homeopathic concept of “like treating like.” 

 Homeopathic vaccinations actually create a balanced and modulated immune protection, creating more regulatory or suppressor T-cells as opposed to the expected imbalances (diminished cellular immunity and heightened autoimmunity) created by the far more toxic injected vaccines with the added immune-irritating adjuvants of corporate conventional medicine. 

  Most vaccinated people end up with depressed cellular immunity (since the skin trigger of cellular immune response was bypassed with the shot) and increased humoral immunity (which means more autoimmune disease and cancer).  Even more insidious, depending on whether the injected medicine ends up in an artery (where it becomes a major immune insult) or the planned muscle or subcutaneous tissue, small percentages of children with weak detoxification systems are much more severely injured. 

  Eve­ry­one knows wa­ter.  It shapes our bod­ies and supports life on our plan­et.  But de­spite the magical liquid’s ever presence, the mo­lec­u­lar struc­ture of wa­ter re­mains a mys­tery.  Wa­ter ex­hibits a strangely var­y­ing dens­ity, large heat ca­pacity and high sur­face ten­sion at tem­per­a­tures which are rel­e­vant to life.

 Com­pared to other li­quids, wa­ter has bizarre prop­er­ties that are still poorly un­der­stood.  The mo­lec­u­lar struc­ture of wa­ter might be com­pared to a crowd­ed club with a dance floor, where pa­rticipants (the mol­e­cules) switch be­tween danc­ing ex­cit­ed­ly and sit­ting in or­derly fash­ion at ta­bles.  Water molecules can form long polymers of dipoles associated by hydrogen bonds and the electromagnetic radiations that they emit enable them to avoid decay. 

 Wa­ter mol­e­cules polymerize them­selves solidly in ice, and form a less-dense tight “te­tra­he­dral” lat­tice, with each mole­cule bind­ing to four oth­ers.  As ice melts, water’s tet­ra­he­dral struc­tures theoretically loos­en their grip globally, break­ing apart consistently as the tem­per­a­ture rises, but all still striv­ing to re­main as tetrahe­dral as pos­si­ble, re­sult­ing in a smooth dis­tri­bu­tion around distorted, par­tially bro­ken tet­ra­he­dral struc­tures. 

 New X-ray studies of liq­uid wa­ter surprisingly found two dis­tinct struc­tures (ei­ther very disordered or very tet­ra­he­dral) that ex­ist no mat­ter the tem­per­a­ture.  The two types of struc­ture are spatially sep­a­rat­ed, with the tet­ra­he­dral struc­tures ex­isting in clusters made of up to about 100 molecules sur­rounded by disor­dered re­gions.  Organized
tet­ra­he­dral water is low-density and chaotic water is higher in density.

 Most “nor­mal” liq­uids be­come dens­er, or molecularly more packed, as they get colder.  Wa­ter however, reaches its max­i­mum dens­ity at about 4 de­grees Cel­si­us.  Above and be­low this tem­per­a­ture, wa­ter is less dense; this is why lakes freeze from the sur­face down. 

 Wa­ter al­so has an un­usu­ally large ca­pacity to store heat, which sta­bi­lizes ocean tem­per­a­tures, and a high sur­face ten­sion, which al­lows in­sects to walk on wa­ter, droplets to form and trees to trans­port wa­ter to great heights. 

 Water is a fluc­tu­at­ing mix of the two molecular organizations at tem­per­a­tures rang­ing from am­bi­ent to all the way to near the boil­ing point.  As the tem­per­a­ture of wa­ter in­creases, few­er and few­er of these clumps exist; but they are al­ways there to some de­gree, in clusters of a si­m­i­lar size.  The disordered re­gions them­selves be­come more chaotic as tem­per­a­ture rises. 

 Clusters of molecules within liquid water have been discovered, identified and characterized that form unique stable (non-melting) ‘ice crystals’ that maintain a vibrational memory of the diluted material as a characteristic subtle electromagnetic field.  These nanometer-sized, rod-shaped water clusters (specific aqueous nanostructures) are created when a substance is placed in distilled water, then vigorously shaken or stirred, and then homeopathically repeatedly diluted ten times while again and again being vigorously shaken or stirred.

  Some bacterial DNA sequences induce electromagnetic waves at high aqueous dilutions (a newly discovered energetic property of DNA).  It seems to be a resonance phenomenon triggered by the ambient electromagnetic background of very low frequency waves. 

 The aqueous solutions were strongly agitated and serially diluted since this step was “critical for the generation of signals”.  Pathogenic bacteria and viruses show a distinct electromagnetic signature at water dilutions ranging from 10(-5) to 10(-12) (corresponding to 5X to 12X) and small DNA fragments (responsible for pathogenicity) are solely accountable for the electromagnetic signal.

  One experiment found significant effects from dilutions as high as 10(-18) (equivalent to 18X).  The electromagnetic signature changed with dilution levels but was unaffected by the initial concentration and remained even after the remaining DNA fragments were destroyed by chemical agents.

 These characteristic frozen crystals of magnetically organized clusters of harmonically vibrating water molecules remain stable at high temperatures, and its intriguing that the ice crystals seem to still exist with varying fluctuation even after 23 repeated dilutions (which is beyond Avogadro’s number, meaning no original molecules of the formerly potent or dangerous diluted substance seem to remain in the diluted and shaken water, only traces of its stored electromagnetic vibrational memory).

  The phenomena of hormesis and toxicity thresholds are likely related to activation of allostatic adaptive pathways responsible for cellular and physiological homeostasis (our ‘steady state’).  Disruption of homeostasis triggers modest overcompensation and the reestablishment of harmonic homeostasis via the adaptive nature of this process. 

 Thus, fasting, heat shock or hot and cold hydrotherapy, pro-oxidants like mega-dose vitamin C, one or two alcoholic drinks per day, plant polyphenols and aldehydes, moderate exercise as well as mild irradiation or sunshine can all be interpreted by our genes as gentle beneficent stressors.

 The key factor in the hormesis concept is not the irritant or chemical, but the organism’s response of overcompensation to a disruption in homeostasis.  Therefore, any agent or stressor can induce a hormetic response, depending on dose.  

 Homeostasis is defined as the maintenance of a constant internal environmental state for efficient functioning and performance of the organism.  However, convincing arguments have been put forward to replace the term homeostasis with homeodynamics, taking into account the harmonic dynamic rhythmic nature of living processes within the ever-changing parabolic wave of life.

 The harmonic vibrational pattern of these internal rhythms inherently resists perturbation.  A critical part of the homeodynamic character of living systems is their capacity to respond and adapt to environmental stress.  In this context, the term "stress" is defined as a signal generated by any physical, chemical or biological factor (stressor), which, in a living system, initiates a series of biochemical events in order to counteract, change and survive by maintaining allostasis (the compensatory steady state).

  Thermoregulation, detoxification, cell proliferation or reduction through apoptosis, DNA repair, heat shock protein synthesis, protein turnover and antioxidative responses are some of the crucial homeodynamic responses.  Often, these survival mechanisms are common to several stresses as well as different species, and have been given a collective term "the general-adaptive syndrome."

 Relatively small individual hormetic effects can become biologically amplified resulting in the collective significant improvement of cellular, tissue and organ functions enhancing survival of the whole organism.   Higher exposure switches cells to a stressed state when allostatic load reaches the limit of homeostatic control.  In the highly stressed state of exhaustion, the immune system typically becomes activated leading to inflammatory responses.

 Cells in adaptive or stressed state can still return to normal, unstressed state after removal of the stressor, depending on duration.  However, very high doses of stressors for too long are likely to drive cells irreversibly to a toxic state, where cells die by apoptosis or necrosis.  

 Apoptosis is an active, programmed self-terminating process of the cell in the event that the cellular damage is too large to be repaired or worth repairing, or the cell’s continued survival no longer benefits the organism as a whole.  As opposed to overwhelming toxicity or excessive inflammation inciting explosive cellular death by necrosis, quiet apoptosis eliminates only damaged parts, while prepackaging cellular components for efficient reclamation and reuse by associated phagocytic white blood cells.

 As early as 1898, studies in radiobiology found that irradiated algae grew more quickly than non-irradiated controls.  Physicians, the public and research scientists showed much interest in the possible beneficial effects of low levels of radiation.

 Such enthusiasms were soon dampened by reports of deaths and severe injury from large amounts of radiation.  After Herman Muller's 1928 publication on genetic damage in fruit flies, radiation became associated with chromosome damage.  Data published in the 1930s-1950s again showed small amounts of radiation to be beneficial to biofilm cellular growth and repair, explained by hormetic concepts.

 Considerable money and effort has been spent to reduce radiation doses to the lowest possible level, since most people have come to believe there is no safe level of radiation.  Some of these efforts may be misplaced, since the radiation fear is based on the incomplete linear ‘no-threshold theory’ of carcinogenesis, which theorizes that "if 1 Gy (100 rad) of exposure gives a cancer risk R, then the risk from 0.01 Gy (1 rad) of exposure is R/100, the risk from 0.00001 Gy (1 mrad) is R/100,000, straight on to infinity.

 According to the errant no-threshold theory, the cancer risk is not zero regardless of how low the exposure (since we are surrounded by ambient radiation).  In terms of imaging exams, a hormetically beneficial back-to-front chest x-ray delivers a surface entrance dose of about 0.02 cGy (rad), at least 100 times lower than the moderately risky dose of 2-5 cGy (rads) of a standard chest CT.

 According to the no-threshold theory, "a single particle of radiation hitting a single DNA molecule in the nucleus of a single cell of the human body can initiate a cancer."  "The probability of such a cancer initiation is theoretically proportional to the number of such hits, which is proportional to the number of particles of radiation, which is proportional to the dose.  Thus risk is proportional to the dose."

 But real-world experience does not jibe with this theory.  Working to prevent most cancers are the body's defense mechanisms.   The body produces enzymes that repair 99.99% of cell damage, and low-level radiation is now known to hormetically stimulate apoptosis, by which damaged or defective cells "commit cell suicide" quietly eliminating themselves before they become tumors.

 Cancer mortality rates actually decrease following exposure to low dose irradiation.  Hormesis (Greek HORMO = I excite) strictly speaking is the beneficial stimulation of any system by low doses of any agent.  Ultra low doses of many agents evoke a biologically positive effect; whereas large doses may produce a harmful effect.  The message is simple: small and large doses often induce opposite physiologic results.

 Radiation hormesis implies beneficial stimulation by small doses of ionizing radiation. Cancer induction is the most feared action of large doses of ionizing radiation.  Cancer mortality rates illustrate radiation hormesis in humans.  Large doses of ionizing radiation harmfully increase cancer mortality rates.

 Since small doses decrease cancer mortality rates, low dose irradiation is surprisingly beneficial.  Although small doses of radiation or dietary stressors like plant polyphenols can stimulate cell and cancer growth, the stimulation of different components of our complex immune system more than compensates for simple cellular effects.  The net effect is decreased cancer mortality.

 Radiation-induced genomic instability, in which the progeny of irradiated cells display a high frequency of nonclonal genomic damage, occurs at a frequency inconsistent with mutation.  In human mammary epithelial cells (HMEC) exposed to low doses of radiation, centrosome deregulation occurs in the first cell cycle after irradiation, is dose dependent, and that viable daughters of these cells are genomically unstable as evidenced by spontaneous DNA damage, tetraploidy and aneuploidy. 

 TGFbeta inhibition significantly increases centrosome aberration frequency, tetraploidy and aneuploidy in nonirradiated HMEC.  Rather than preventing radiation-induced or spontaneous centrosome aberrations, TGFbeta selectively deletes unstable cells (which might become cancer) via p53-dependent apoptosis.  Radiation deregulates centrosome stability, which underlies genomic instability in normal human epithelial cells, and that is opposed by low-dose radiation-induced TGFbeta signaling.

  A study of naval shipyard workers who serviced nuclear-propelled ships compared workers who were and those who were not occupationally exposed to radiation.  Workers exposed to the highest levels of radiation (> 0.5 cSv) had cancer mortality rate that was only 85% of the rate experienced by workers who were not exposed.  The most convincing finding was the very significant decrease of 24% in deaths from all causes among workers exposed to the highest doses (U.S. Dept of Energy, 1991).

 A study of lung cancer rates among women exposed to fluoroscopic examinations for TB came to similar conclusions.  Lung cancer rates among these Canadian women, as well as a one-point study of 10,000 tuberculosis patients in Massachusetts, showed a protective effect up to 20 cSv and 100 cSv (Radiation Research, June 1995, Vol. 142:3, pp. 295-304; and Cancer Research, November 1989).

 Radiation-induced noncancer health effects are not detectable for fetal doses below about 50 mGy (1 mGy =100 milli rad).  Noncancer health effects may be expected after fetal doses >=100mGy and appear to have the most significant effects between the gestational ages of 8-25 weeks.  Dental x-rays barely reach the fetus (except in a hormetic way) at .001 rads.

  An average chest x-ray delivers only .00007 rads.  A single mammogram film, on the other hand, delivers .1-.2 rads.  If two mammogram films are taken of each breast, then that means that a breast would receive about .001 rads during a chest x-ray as opposed to about .2-.4 rads with a mammogram. This means that a mammogram procedure can be 250-500 times more intense than a chest x-ray, if no extra films are requested for clarification. 

  Repeated mammograms do not improve survival rates and are associated with an increased risk to cancer.  Perhaps it is not the radiation.  Some believe that the compression force used may rupture existing cancer cells that are contained in a localized mass, and cause malignant cells to be released into the bloodstream, thereby promoting metastatic cancer.  Thermograms are a safer alternative and make more sense because they can pick up an area that is cold or hot, before it has actually turned into cancer.  Mammograms farm for industry and find established cancers.  Thermograms can prevent them.

  Summary of the effects of chronic, whole body radiation exposures on four physiologic functions: Beneficial radiation hormesis rises with up to a 100 fold increase in ambient levels of radiation.  Positive effects are represented by the defined area above the horizontal line.  When compared with controls, represented by the horizontal line, larger dose rates exert a negative effect.  Conclusion: “The linear no-threshold theory fails badly in the low-dose region, because it grossly overestimates risk from low-level radiation.  This means that cancer risk from diagnostic X-rays is much lower than is usually estimated, maybe zero." 

 

 

  This curve represents the classic hormetic response to stressors, the most common form of the hormetic dose-response curve depicting low-dose stimulatory and high-dose inhibitory responses, the b- or inverted U-shaped curve.   Just the opposite may occur with the hormetic dose-response curve depicting low-dose reduction and high-dose enhancement of adverse effects, the J- or U-shaped curve.

 Minimal dose detectable by chromosome analysis is 5-25 rads.  Typical chest X-ray with two views is 1/20 rad.   A cervical or thoracic spine study with multiple views is about ½ rad.   Lumbar spine views dose us with 2 rads and a routine GI study with fluoroscopy is 5-10 rads.  Head CT (measured at the center of a phantom) is 6rads; body CT (measured at the periphery of a phantom, 1 cm beneath the surface) is 4 rads. 

As reported in Natural News, a study in the medical journal Radiology found that people who had numerous CT scans over their lifetime had a significantly increased risk of cancer.  In fact, many CT scans increased the risk to cancer by 2.7-12%. 

 Many medical imaging techniques, including cardiac angiography and CT scans, often involve the use of contrast agents, substances that contain iodine (like iopamidol and iodixanol) and barium, because they enhance the contrast between body structures or fluids within the body. This allows blood vessels and changes in tissues to be more clearly visualized.

 Exposure to contrast agents can cause damage even in seemingly healthy kidneys, but patients are typically assured this is just a temporary side effect that will resolve on its own.  If followed a year or two after imaging with contrast however, 13% of patients experience a major event, such as death, stroke, heart attack or end-stage renal disease.  Those who developed contrast-induced kidney injuries had twice as many long-term negative health effects as compared with patients who did not suffer kidney damage. 

 The average total background radiation of about 1/3 rem per year roughly compares to having 7 (2 view) chest x-rays!  (Another example of how low the exposures are for many diagnostic x-rays!)

  Intra-oral (cavity-detecting dental bite-wings using film) measured exposure at skin entrance averages 250 milli rads.  If skin doses are compared, many medical offices could produce all 7 cervical spine films in a comprehensive study for less skin dose radiation than one or two traditional bite wing films!  Intra-oral (digital) average is about ¼ less, at around 70 milli rads. 

 Cephalometric (film) skin entrance is usually just 15 milli rads, similar to the chest. Literature reports that the effective dose of a panoramic slitted view is but 0.3-1 milli rads.  Jet flight exposes us to ½-1 mrem / hour in the air and luggage inspection 0.002 mrem.

 Endogenous ligands for many receptors exhibit similar parabolic or biphasic dose-response curves, with high doses being toxic.  A prime example is glutamate, the major excitatory neurotransmitter in the brain.  In low to moderate amounts that are released from presynaptic terminals during the normal activity of nerve cell networks, glutamate mediates processes such as learning and memory and sensory-motor behaviors.

 Binding of glutamate to its receptors causes membrane depolarization and calcium influx through ligand-gated and voltage-dependent calcium channels.  The beneficial effects of low to moderate levels of glutamate receptor activation result from calcium-mediated activation of transcription factors such as nuclear factor (NF)-κB and CREB (cyclic AMP response element binding protein) that induce the expression of genes that encode proteins that promote the survival and plasticity of neurons including brain-derived neurotrophic factor (BDNF) and the anti-apoptotic protein Bcl-2.

 However, excessively high levels of glutamate can overwhelm any hormetic pathways and kill neurons by a process called excitotoxicity.

Mercury

 Mercury deserves special mention since it is the most toxic non-radioactive substance in our environment.  At low micromolar concentrations, mercury uncouples tubulin, a structural protein necessary for nerve formation and synapses as well as chromosomal reorganization during reproductive meiosis and mitosis.  There seems to be almost no safe level (smallest micromolar amounts are hormetic, less than ten millionths) of elemental mercury.  Only very high homeopathic dilutions have clinical use, usually to calm irritability and combativeness, relieve pain or aid detoxification of mercury.

 Bacteria are even more vulnerable to damage from mercury than us.  Before the age of antibiotics, mercury was often used to treat syphilis.  Doctors of the day noted initial salutary effects before toxicity took over.  People who were dull and phlegmatic became passionate about the issues of life, even to the point of becoming combative.  Now that we understand how dangerous elemental mercury is, background exposure is already higher than beneficial hormetic levels (just like fluoride).  However, at the homeopathic vibrational level, benefit can be created just from the energetic imprint of mercury left in the electromagnetic memory of water.

Fluoride

 The range of fluorine-containing compounds is considerable as fluorine is capable of forming compounds with all the elements except helium and neon.  Structurally, and to some extent chemically, the fluoride ion resembles the hydroxide ion.  In biochemistry, fluoride salts are commonly used to inhibit the activity of phosphatases, such as serine/threonine phosphatases.   It may do this by replacing the nucleophilic hydroxyl ion in these enzymes' active sites.

 The mechanism of toxicity involves the combination of the fluoride anion with the calcium ions in the blood to form insoluble calcium fluoride, resulting in hypocalcemia; calcium is indispensable for the function of the nervous system, and the condition can be fatal.

 Fluoride-containing compounds are used in topical and systemic fluoride therapy for preventing tooth decay.  They are used for water fluoridation and in many oral hygiene products.   Originally, sodium fluoride was used to fluoridate water; however, the waste-product hexafluorosilic acid and its salt sodium hexafluorosilicate are more commonly used additives, especially in the U.S.  Public health officials worsened the situation by adding fluoride (its current industrial waste source also increases the amount and absorptive availability of lead, arsenic and aluminum) in our water.  Fluoride ingestion or absorption/inhalation greatly enhances uptake of radioactive elements, including iodine 131 and strontium 90. 

 The fluoridation of water has been ‘scientifically proven’ (with the backing of the biggest fluoride polluters) to prevent tooth decay and is considered by the U.S. Centers for Disease Control and Prevention as "one of 10 great public health achievements of the 20th century".

 It is a common theory that the reason fluoride was proven to reduce tooth decay in Michigan (a glaciated area low in soil iodine, where hypothyroidism is endemic) was through a statistical trick.  The key statistical dental parameter improved (in Michigan) by adding one part per million fluoride in community water was decayed, extracted or filled 6 year molars.  Degrees of hypothyroidism progressively delay the eruption of teeth.  Fewer teeth results in fewer cavities.

 The amount of fluoride a modern American gets from fluoridated water and contaminated foods is the amount German physicians sometimes still use today to poison the thyroid to treat hyperthyroidism.  Further fluoride competition (with already low iodine) accentuated subclinical hypothyroidism and delayed eruption of studied ‘6 year’ molars (perhaps slowed as much as a year) and accounted for statistical improvement of decay scores.  Delayed eruption of teeth was interpreted as a "benefit" in fluoridated areas when same-age children's teeth were compared.

Fluoridation of water is however (especially since there is now so much in the environment), not without critics.  Russell L Blaylock, MD notes that fluoride is strongly associated with damaging DNA, interfering with thyroid function leading to hypothyroidism, creating problems with fluoridated organic molecules (Paxil, Prozac and some antibiotics), significantly increasing many types of cancer, increasing heart disease, increasing oral cancer and even periodontal disease, reducing zinc in body tissues (including the brain), increasing Down's Syndrome, reducing testosterone and sperm count, increasing Alzheimer's and lowering IQ.

Perfluorinated chemicals, (pervasive in food packaging, pesticides, clothing, upholstery, carpets and personal care products), may delay pregnancy.  These chemicals are also commonly used in non-stick cookware.  Using non-stick cookware encourages ingesting perfluorinates, which are being phased out in the U.S. because of their toxicity.  However, they remain in the environment and in the body for decades, and are linked to developmental problems.  Danish women with high levels of perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) take longer to get pregnant. 

Women in the three groups with the highest levels of PFOS took from 70-134% longer to get pregnant than women in the lowest quartile with the lowest PFOS levels.  Women with the highest PFOA levels took 60-154% longer to get pregnant compared with women with lowest levels.  In animals, these chemicals have a variety of toxic effects on liver, immune system and developmental as well as reproductive organs, also inducing impaired fetal growth.

Environmental contaminants such as PCBs, PBDEs, and mercury can alter brain neuron functioning even before a child is born. These changes to the brain can be long-lasting. Stain-resistant chemicals, found in up to 98% of Americans sampled in the late 1990s, are found in clothing, carpeting, upholstery, and even the lining of food containers.

Hormone-like vitamin A also has hormetic effects.  Vitamin A in relatively low amounts is essential for normal development, immunity and eye function, but in high amounts can cause anorexia, dry skin, headaches, drowsiness, altered mental states and immune suppression.

  Studies on the use of the stressor alcohol have shown hormetic protective effects against coronary heart disease.  These studies show that one or two alcoholic drinks per day increases high-density lipoproteins.  Also, moderate alcohol consumption decreases low-density lipoprotein (LDL) cholesterol and triglycerides.  Finally, alcohol consumption decreases platelet aggregation.

  Red wine has benefits that other sources of alcohol do not have.  Red wine reduces C-reactive protein, a marker of inflammation related to atherosclerosis and cancer.  Red wine has higher concentrations of antioxidant molecules, called polyphenols, than other alcoholic drinks, which protect against coronary heart disease by reducing oxidation of LDL cholesterol.   The polyphenols in red wine include anthocyanins, proanthocyanidins and resveratrol, as well as flavonoids, including catechins, kaempferol and quercitin. 

 Twelve healthy subjects imbibed either a vitamin-enriched beverage twice daily or the same vitamin-enriched beverage supplemented with an additional 500 mg of the plant-based flavonoid quercitin.  Over a week-long period, participants were monitored to assess the amount of time it took to show fatigue during a stationary bike riding session, as measured by VO2max (also known as maximal oxygen consumption), a marker of physical fitness that measures maximal capacity of the body to use and transport oxygen during exercise.

 Supplementing with quercitin mimics exercise training in that it increased VO2max by 3.9% compared to placebo, a marginal improvement.  However, fatigue times told a very different story.  Those who received a quercitin boost showed a significantly higher 13.9% increase in physical stamina during bike-riding exercise.

 Red wine tends to reduce mutagenic DNA damage and improve endothelial function when included in a high fat diet.  Wine can stimulate gastric acid secretion and gastrin release.  Perhaps this is why moderate to high wine intake seems to prevent Helicobacter pylori infection.   Red wine may help to prevent noise-induced hearing loss, reduce the risk of developing age-related macular degeneration, may help to prevent cataracts and may help prevent rheumatoid arthritis.

  Many studies suggest salutary roles of dietary phytochemicals produced in survival response to stress in protecting against chronic disorders.  Several dietary phytochemicals also benefit the nervous system and, when consumed regularly, reduce the risk of disorders such as Alzheimer’s and Parkinson’s diseases.  Not all grapes (nor red wines) contain the same amount of resveratrol.  Because resveratrol is created by the grape plant primarily in response to fungus, grapes that are sprayed with fungicides produce virtually no resveratrol.  Only organically-grown plants produce the highest levels of resveratrol.

  One general mechanism of action of phytochemicals is that they activate hormetic adaptive cellular stress-response pathways.  From an evolutionary perspective, the noxious properties of such phytochemicals play an important role in dissuading insects and other pests from eating plants.  However at the relatively small doses in plants ingested by humans, the phytochemicals are not toxic and instead induce beneficial strengthening through mild cellular stress responses.

  Hormesis has been widely observed in biology and medicine, and has been described as ‘preconditioning’.  Hormetic pathways activated by pigmented phytochemicals may involve kinases and transcription factors that induce the expression of genes that encode antioxidant enzymes, protein chaperones, phase-2 detoxifying enzymes, neurotrophic factors as well as other protective proteins.  A family of histone deacetylases called sirtuins has played pivotal roles in stress resistance through a vast expanse of evolutionary history. 

  Specific examples of such pathways include the life-extending sirtuin–FOXO pathway triggered also by calorie restriction or resveratrol, the protective (when tethered) proinflammatory NF-κB pathway and the Nrf-2/ARE pathway, which upregulates expression of phase II detoxifying enzymes and antioxidants, thus enhancing elimination of noxious stimuli.  Hormetic phytochemical actions of the Nrf-2/ARE signaling pathway are a classical expression of a neuroprotective mode of action of many specific dietary phytochemicals.

  The term hormesis is commonly used by toxicologists to describe the parabolic or biphasic dose response curve where a chemical may have a beneficial stimulatory effect at ultra low doses, but become harmfully toxic at high doses.   This has led some to argue that environmental health standards can be relaxed because if low doses are beneficial, then there is no need to achieve stringent cleanup standards.  However, low doses can sometimes have surprising impacts that cannot be predicted from high dose experiments.

Hormesis as a programming modifier

 Bisphenol A is moderately toxic at high doses and at ultra-low doses has even more problematic hormone-like effects, (literally changing gene expression, sometimes at critical developmental phases).   Higher toxicological doses of estrogenic compounds like estradiol and bisphenol A act as a hormone mimic through estrogen receptors, and can actually turn off genes turned on by lower doses. 

 Traditional high dose testing misses many low dose adverse effects.   Current testing procedures are vulnerable to dramatic under-estimations of health risks because of lack of knowledge of molecular details of just how endocrine disruption of estrogenic signaling actually works.

 High doses of the estrogenic drug diethylstilbestrol cause weight loss in adults following exposure in the womb.  Lower doses (within the range that lead to a wide array of adult disorders of the reproductive tract) have no effect on adult weight.  But doses far lower than those (1 ppb) cause grotesque obesity.

 

Atrazine

 For decades, farmers, lawn care workers and professional green thumbs have relied on the popular weed killer atrazine to protect their crops, golf courses and manicured lawns.  But atrazine often washes into water supplies and has become among the most common contaminants in American reservoirs and other sources of drinking water. 

 

 At high doses, atrazine is a neurological poison that can lead to Parkinson’s disease and is detoxified by the cytochrome P450 enzymes (which have great individual variability), specifically CYP1A2.  Caffeine, melatonin, diflucan, clozapine and many other drugs are oxidized for detoxification by this enzyme, and may overload the system. 

 

 Drugs like artemisinin or ethynil estradiol that inhibit CYP1A2 will predictably increase the plasma concentrations of atrazine and many medications and in some cases adverse outcomes will occur.  Of particular note is fluvoxamine, which is a potent CYP1A2 inhibitor and also inhibits other CYP450 enzymes, such as CYP2C19, the most important CYP3A4, and to some extent CYP2C9.  Thus, fluvoxamine may prevent other metabolic pathways from compensating for the CYP1A2 inhibition.  The fluoroquinolone antibiotics, enoxacin and ciprofloxacin, also substantially inhibit CYP1A2.

 

  Cigarette smoking upregulates and induces CYP1A2 enhancing detoxification of atrazine or reducing beneficial levels of theophylline.  Smoking, grilled meat and cruciferous vegetables or barbiturates also reduce the serum concentrations and efficacy of the atypical antipsychotics, clozapine and olanzapine.

 

  In recent years, five epidemiological studies published in peer-reviewed journals have found evidence suggesting that small amounts of atrazine in drinking water, including levels considered safe by federal standards, may be associated with birth defects — including skull and facial malformations and misshapen limbs — as well as low birth weights in newborns and premature births.  Such defects and premature births are leading causes of infant deaths.

 

 Some studies note that as atrazine concentrations rise, the incidence of birth defects grows.  One study done at Purdue University, published in the journal Environmental Health Perspectives — suggests that concentrations as small as 0.1 parts per billion may be associated with low birth weights.

 

 Atrazine may be safe during many periods of life but dangerous during brief windows of development, like when a fetus is growing and pregnant women are told to drink lots of water.  There are short, critical times (like when a fetus’s brain is developing), when chemicals can have disastrous impacts, even in very small concentrations.

 

 The E.P.A. generally does not require water systems to notify residents unless the yearly average of atrazine in drinking water exceeds 3 parts per billion, and under a determination made earlier this decade, the agency considers one-day exposures of up to 297 parts per billion safe.

 

 Another study suggests that concentrations of atrazine in drinking water below the E.P.A. thresholds may disrupt menstrual cycles.  Many of those studies examined large populations already exposed to atrazine and sought to exclude the effects of other contaminants and environmental or health factors.  However, such epidemiological studies cannot prove that atrazine causes specific diseases.

  The concept of hormesis has been adopted in the fields of biology and medicine to describe the adaptive response of cells and organisms to moderate stress.    Mild stress induces the activation of signaling pathways, leading to intrinsic changes conferring resistance to more severe stresses.  Usually, the stressor elicits molecular responses that not only protect the cell against higher doses of the same agent, but also against other agents or even less specific stressors including oxidative, metabolic and thermal stress.  

  Major components of the hormetic response include various stress resistance proteins such as heat-shock proteins (which AGEs mimic), antioxidants and growth factors.  Besides AGEs in caramels or toast, classic examples of hormetic stress are hot and cold hydrotherapy, exercise and calorie restriction.  Studies have consistently demonstrated that moderate levels of exercise and calorie restriction promotes good health, where higher levels are harmful.

 Growing plants need protection against radiation, bacteria, fungi, viruses and hazardous environmental changes.  Plants concentrate defensive chemicals in their most vulnerable parts: leaves, flowers and roots.  Like the mild stress of a cold shower, an alcoholic beverage or two, moderate exercise or fasting, many of these plant ‘poisons’ also exhibit hormetic properties, being harmful at high individual doses yet being especially beneficial at harmonic combinations at dietarily relevant low doses from herbs, vegetables and fruit as well as soaked seeds, beans, nuts and grains.

  The hormetic non-linear biphasic dose-response exhibits a parabolic curve.  A hormetic response is a special case of a larger set of dose-response curves called ‘non-monotonic dose-response curves’, because the slope of the curve changes direction somewhere along the curve.  Thus, J-shaped or U-shaped or inverted-U shaped parabolic curves are all non-monotonic.

 Curves contrast with linear monotonic responses (where an incomplete range of dilutions are tested, creating a small linear section of a larger parabolic curvilinear response) in which the slope never changes sign (in other words, if the curve or line is upward it always remains upward (although it can change slope and flatten out).

 Hormesis can be initiated by exposure to various environmental stressors including ingestion of phytochemicals.  Such exposures typically result in mild cellular stress involving free radical production, ion fluxes and increased energy demand.

  As a result, adaptive stress response pathways are activated leading to the synthesis of proteins that protect the organism against more severe stress.  Examples of stress resistance proteins include antioxidants, protein chaperones, growth factors and proteins involved in the regulation of energy metabolism as well as cellular calcium homeostasis.

 The amounts of stress-inducing phytochemicals found in the fruits and vegetables usually consumed by humans fall within the low-dose beneficial stimulatory range of concentrations.   However, it is well-known that some plants and fungi produce and concentrate toxins in amounts great enough to cause sickness or death in humans.

  Consumption of plant phytochemicals in form of concentrated supplements has the potential for negative health consequences if the doses consumed exceed toxic threshold.  Each individual phytochemical would best be extensively evaluated (and then in combinations), including detailed dose-response studies that reveal safety and effectiveness in regard to disease prevention.  Low-dose extrapolations employed in risk assessments will have to stay wedded to the low-dose linear and threshold methodologies that are now favored until much more research is done.

 Combinations of stimuli can have unpredictable outcomes.  Mild to moderate exercise derives its hormetic effect from the production of stressful reactive oxygen species.  Moderate doses of antioxidant vitamins can ‘mop up’ these mildly stressful oxidants, cancelling the benefit of exercise.  Paradoxically, large doses of antioxidant supplements increase oxidative stress, hormetically increasing tolerance to other stressors.

 UV hormesis can be thought of as an induced effect that occurs over intervals of time measured in hours or days, in contrast to the virtually instantaneous damaging effects of UV on DNA.  It relies on eliciting a metabolic response by the plant tissue in countering what it perceives as an applied stress. The response is chemical.  For certain types of fruit, the compounds produced as a result of low-dose UV treatment have been identified, including a wide range of phytochemicals and enzymes.

 The critical factor is that these compounds confer resistance to attack by many different types of microorganisms, and molds in particular.  More importantly, these naturally occurring compounds and microbial inhibition can be achieved without the use of exogenous biocides.  Many species of fruits and vegetables have been shown to respond to this form of treatment.

 In commercial terms, this stress response offers a way to extend the shelf life of fresh commodities. Hormetic treatments also have the potential to reduce waste through decreasing the rate of senescence.  However, much work remains to be done in scaling up laboratory studies to enable hormetic treatments to be applied commercially.

  There is another benefit of hormetic treatment, and that is that many of the compounds produced by the plant in response to UV are actually beneficial to human health.  The best studied example is resveratrol in grapes (where recent work has shown that the levels of this cardio-protectant may be increased many fold by treating grapes with low doses of UV).

  The lethal effects of UV used as a germicide may be increased by combining UV treatment with the use of powerful oxidants, such as hydrogen peroxide and/or ozone.  Although both of these compounds are moderately bactericidal in their own right, the added effect of UV is to bring about a synergistic inactivation through the enhanced generation of highly reactive free radical species.

  Ozone has been assigned the classification “generally recognized as safe” (GRAS), but hydrogen peroxide residuals can persist in foods for considerable periods of time.  This may prove problematic in the treatment of foods, as opposed to food processing equipment, or even the fabric of food processing facilities.  Careful control of peroxide concentration and UV dose is required to ensure total photolysis of peroxide.

The evidence supporting health benefits of vegetables and fruits provides grounds for identification of the specific phytochemicals responsible, and for investigation of their molecular and cellular mechanisms of action.  Practically all plants provide felicitous phytochemicals, here are a few:

 The primary polyphenol found in flesh of grapes and concentrated in white grape juice, hydroxycinnamic acids (also major phenolic acids in blueberries and blackberries) are a superset of phenolic acids which includes p-coumaric, caffeic and ferulic acid (major phenolic acids in blueberries and blackberries).  Ferulic acid is abundant in cell walls of seeds of brown rice, whole wheat and oats and rich in apple, artichoke, orange, peanut and pineapple. 

 Ferulic acid is precursor to vanillin and is antioxidant and anticancer, exhibiting antitumor activity in breast and liver cancer.  Vanillin (primary extract from vanilla bean) is antimutagenic and antioxidant, inhibits carcinogenesis, is anti-inflammatory (inhibits peroxynitrite) and inhibits double-strand DNA breaks.  Cinnamic acid (phenyl acrylic acid) provides oil of cinnamon's characteristic odor and flavor.  It has antibacterial, antifungal and antiparasitic properties.  Cinnamic acid is building block for lignans.

 Ferulic acid is found in the leaves and seeds of many plants, but especially in cereals such as brown rice, whole wheat and oats.  Ferulic acid is also present in tomatoes, sweet corn, coffee, apple, artichoke, peanut, orange and pineapple.  Ferulic acid decreases the levels of inflammatory mediators (prostaglandin E2 and TNF-α and nitric oxide synthase expression and function.  Ferulic acid and its esters are potentially powerful anti-inflammatory drugs.  Ferulic acid belongs to the family of hydroxycinnamic acid.  The chemical structure of ferulic acid is very similar to that of curcurmin.

 Curcumin (diferuloylmethane) is a component of the yellow powder prepared from the roots of Curcuma longa (Zingiberaceae), also known as tumeric or turmeric.  It is widely cultivated and used as a food ingredient in tropical areas of Asia and Central America.

 Treatment of mid-passage human epidermal keratinocytes with curcumin resulted in a biphasic hormetic dose–response with respect to proteasome activity.  Curcumin treatment (up to 1 μM for 24 h) increased chymotrypsin-like activity by 46% compared to that in untreated keratinocytes.  However, higher concentrations of curcumin were inhibitory, and at 10 μM the proteasome activity decreased to 46% of its initial value.

 Furthermore, the preincubation of human keratinocytes at 43°C for 1 h, followed by 24-h treatment with 3 μM curcumin, led to an increase in heat-shock protein (hsp70 and hsp90) levels by 24% and 19%, respectively, and the effect was sustained at concentrations up to 10 μM.  On the other hand, the level of the small hsp27 was unaffected by curcumin concentrations of 0.3–1 μM, while it decreased by 34% at 10 μM.

    Chalcone is an α, β-unsaturated aromatic ketone present in ashitaba (Angelica keiskei Koidzumi), a white turmeric traditionally used in Japanese’s cuisine.  Chalcone has antibacterial, anti-fungal, anti-tumor and anti-inflammatory activities.  The anti-inflammatory effects of chalcones rely on their ability to regulate nitric oxide and cytokine production in macrophages, as well as to prevent tumor necrosis factor-α and lipopolysaccharide-induced neutrophil adhesion.  Chalcone also suppresses the activity of cycloxygenase-2 and 5-lipoxygenase.  Blood sugar leveler methyl hydroxychalcone is found in cinnamon.  Hops contain chalcones, xanthohumol and dehydrocycloxanthohumol hydrate.

 Polyphenol compounds found in green tea include epigallocatechin-3-gallate (EGCG), epicatechin-3-gallate (ECG), epigallocatechin (EGC) and epicatechin (EC), and their intake has been associated with reduced risk of coronary artery disease.  EGCG is the most abundant and active catechin derivative, and has been shown to possess both anti-inflammatory and anti-atherogenic properties.   EGCG up-regulates hemeoxygenase-1 (HO-1) expression by hormetically activating the Nrf2/ARE pathway in endothelial cells, conferring resistance against H2O2-induced cell death.

 Luteolin is a widespread citrus flavonoid aglycon structurally related to quercitin.   Most often found in leaves, but it is also seen in dandelion, rinds, barks and clover blossom and ragweed pollen.   Dietary sources include celery, green pepper, thyme, as well as perilla and chamomile tea.  Topical application of luteolin causes significant reduction of skin tumor incidence and multiplicity in a mouse model.  In cell culture studies, luteolin has been shown to be a potent inhibitor of cyclin-dependent kinases, to induce cell cycle arrest in human melanoma cells and apoptotic cell death in human myeloid leukemia cells. Luteolin also sensitizes cancer cell lines to TNFα-dependent apoptosis by inhibiting the NF-κB pathway. In addition to anticancer properties luteolin has also shown to protect neuronal cell lines against H2O2 induced oxidative damage.

  Phenethyl isothiocyanate occurs naturally in cruciferous vegetables such as Chinese cabbage, turnips, rutabagas, watercress and radishes.  Isothiocyanate is liberated from its glucosinolate precursor gluconasturtiin by hydrolysis following disruption (crushing, shredding and chewing) of the plant tissue and liberation of the plant enzyme myrosinase.  Glucosinolates have been shown to inhibit the tumor causing effects of various carcinogens.  Sulforaphane is a related phytochemical present in high amounts in broccoli sprouts and cruciferous vegetables.

 Piceatannol isolated from the seeds of Euphorbia lagascae, is a structural homolog of resveratrol and both are found in red wine.  Piceatannol is an anti-inflammatory, immune modulatory and anti-proliferative compound.  Piceatannol inhibits the release of nitric oxide, PGE2 and pro-inflammatory cytokines in a dose-dependent manner.  The protective effect afforded by piceatannol is reportedly stronger than the effect of resveratrol. 

 Life extension and neuroprotective effects of resveratrol have been reported by many different researchers.  It protected cultured PC12 neural cells against Aβ toxicity and dopaminergic neurons in midbrain slice cultures against several different insults.  Resveratrol also protected hippocampal neurons against nitric oxide-mediated death, prevented axon degeneration and protected nematode and mammalian neurons against mutant polyglutamine toxicity. 

  Resveratrol was found in varying amounts between 7- 5800 ng/g dry sample in bilberry, cranberry, deerberry, Elliott's blueberry, highbush blueberry, lingonberry, lowbush blueberry, rabbiteye blueberry, sparkleberry and Partridgeberry.  Lingonberry was found to have the highest content comparable to that found in grapes, 6500 ng/g dry sample.

 Seanol is a unique patented polyphenol/phlorotannin extract from Ecklonia cava marine red/brown algae grown off the coasts of Korea and Japan.  Polyphenols, which are antioxidants found in many land-based products such as berries, tea leaves, grapes, pomegranates, fruits, and vegetables (and in Seanol), have a molecular structure of two to four connected rings.  These rings “trap” damaging free radicals.

 Trans-resveratrol from red grapes has a two-ring molecular structure and, green tea has a four-ring molecular structure.  However, Seanol has similar polyphenols and phlorotannins, which have a more sophisticated molecular structure of eight rings, which allows it to trap many more free radicals.

 Seanol is both water and fat soluble, so it can easily penetrate phospholipid membranes, working inside of cells for maximum protection.  Even better, it easily crosses the blood/brain barrier to give the brain extra antioxidant protection.  Since Seanol is fat soluble, it stays in the body longer, as much as 12 hours, compared to water soluble antioxidants which are excreted in the urine in roughly 30 minutes.

 Seanol helps increase brain alpha waves, a good indication of relaxing blood vessels to the central nervous system and increasing blood flow, promoting brain activity as well as increasing energy and endurance.  Seanol also helps stimulate the production of acetylcholine, the brain chemical of learning and memory as well as the neurotransmitter that modulates and reduces immune inflammatory response in the digestive system, joints and arteries via the vagus nerve.

  Blueberry supplementation prevented learning and memory deficits in a mouse model of Alzheimer’s disease.  Dietary supplementation with blueberry extract increased the survival of dopamine-producing neurons in a model relevant to Parkinson’s disease.  Blueberries extract increased thermal stress resistance and increased lifespan in the nematode, suggesting an evolutionary conservation of phytochemical hormetic response pathways.  Supplementation of the diet of 19 month-old rats with strawberry, blueberry or spinach extracts for 8 weeks resulted in the reversal of age-related deficits in several neuronal and behavioral parameters.

  In an animal model of stroke, curcurmin (from turmeric) protected neurons against ischemic cell death and ameliorated behavioral deficits.  In a rat model of Parkinson’s disease, curcurmin protected dopaminergic neurons against 6-hydroxydopamine toxicity.  A hormetic mechanism of action of curcurmin is likely since levels of expression of the stress response protein HO-1 were increased in cultured hippocampal neurons treated with curcurmin.  Curcurmin also has been shown to reverse chronic stress-induced impairment of hippocampal neurogenesis and increase expression of brain-derived neurotrophic factor in an animal model of depression.   Wild ginger is also a likely candidate for a hormesis effect.

  The radium pad (low dosage radiation) is an example of hormesis from the Edgar Cayce readings.      The Cayce readings often extolled the healing properties of olive oil.  The following story illustrates an unusual application involving very small amounts of olive oil taken orally for acid reflux (often caused by large amounts of fat or oil):

    "Seven years ago I had my gallbladder removed because of gallstones, and within a few months I began to have acid reflux (heartburn).  TUMS relieved it, but within a couple years I was up to four of the largest size TUMS a day.  Preferring to interfere with my digestive physiology as little as possible, I didn't want to take any of the acid blocker medicines that are now available.

 Instead, I recalled that the Cayce readings had said that olive oil taken in very small doses would be soothing and healing to the digestive system, along its entire length.  For example, reading 5422-2, given for ulcers, said to take a half teaspoonful every few hours.  Another reading, 760-7, for impacted colon, explained that, "This character of oil, as seen, is food value for tissue that is deadened by inactivity through the form of conditions existent in system."  The readings were clear that small doses would be the most effective, no more than a half a teaspoonful taken every few hours.

  "I began to take very small doses of extra virgin olive oil (no more than a quarter or half of a teaspoon about 4- 5 times a day), based on the most common recommendation in the readings.  Within a couple weeks I noticed that I had less need of TUMS.  After a few months, I was down to needing at most one TUMS a day, and most days no medicine at all.  My overall digestion felt a lot better, too.

  Aging is primarily the result of a failure of maintenance and repair mechanisms.  Hormesis is a promising approach for modulating aging and age-related diseases via modest stimulation of various cellular and biochemical functional characteristics of human skin fibroblasts. 

 Beneficial effects include the maintenance of a favorable stress protein profile, reduction in the accumulation of oxidatively and glyco-oxidatively misfolded damaged proteins (AGEs), stimulation of the proteasomal activities for the degradation of abnormal proteins, improved cellular resistance to other stresses and enhanced levels of cellular and mitochondrial antioxidant ability.

  The progression of cellular aging can be slowed without upsetting the regulatory mechanisms of the cell cycle by using the body’s intrinsic capacity for self-maintenance and repair, where through protective low-dose toxin hormetic effects, the quality of life of cells in terms of their structural and functional integrity can be improved without pushing them into a potentially carcinogenic hyper-proliferative mode.

  Progressive accumulation of molecular damage to human skin fibroblasts and keratinocytes, a hallmark of cellular aging, is thus treatable by targeted biological hormetic interventions and preventions. Application of hormesis as an anti-aging approach is gaining wide recognition and acceptance.  Various chemical stressors, including oxidants, both synthetic and natural (such as hydrogen peroxide and 1,4-dioxane) are reported to delay aging and prolong life in various systems, when they act as hormetins.

  Almost all antioxidants show hormetic dose response and become pro-oxidants above certain doses. Furthermore, in some cases such as alpha lipoic acid and coenzyme Q10, it is their pro-oxidant activity in producing hydrogen peroxide (which induces defensive responses), which is the sources of their overall beneficial effects.

 Hormesis is a common phenomenon in dermatology.  Skin is an excellent hormesis candidate due to its repertoire of inflammatory and immune-modulating cytokines, hormones and vitamins, as well as its unique responses to ultraviolet light, toxins and injury.  More focus could be redirected from looking only at adverse effects at high levels of exposure to characterizing the complex beneficial biological effects that occur at low and ultra low levels of exposure.

 Molecular mechanisms facilitating hormetic effects comprise of a cascade of stress response maintenance and repair pathways.  Although the extent of immediate hormetic effects after exposure to a particular stress may only be moderate, chains of events following initial hormesis can lead to biologically amplified effects that may be much larger, synergistic and pleotropic.  

 The consequence of hormetic amplification is increased overall cellular and systemic defense capacity of the organism.  Exposure to low doses of potentially harmful agents can have a variety of beneficial anti-aging and longevity-extending hormetic effects.   Too much stress can overwhelm and exhaust, but the right amount can increase strength and endurance, prolong life and bring other benefits.

Just about any stimulus can be beneficial or harmful,

depending on dose, duration, perception and individual response.

Steven N. Green, DDS, 10261 SW 72 St., #106, Miami, FL, 33173, 305-273-7779

ddsgreen@bellsouth.net   antiagingdentist.com

September 26, 2009