Hormesis

A very low dose of a chemical agent may trigger from an organism the opposite response to a very high dose.

Hormesis (from Greek hórmēsis "rapid motion, eagerness," from ancient Greek hormáein "to set in motion, impel, urge on") is the term for generally favorable biological responses to low exposures to toxins and other stressors. A pollutant or toxin showing hormesis thus has the opposite effect in small doses as in large doses. A related concept is Mithridatism, which refers to the willful exposure to toxins in an attempt to develop immunity against them.

In toxicology, hormesis is a dose response phenomenon characterized by a low dose stimulation, high dose inhibition, resulting in either a J-shaped or an inverted U-shaped dose response. Such environmental factors that would seem to produce positive responses have also been termed “eustress”.

The hormesis model of dose response is vigorously debated.^[1] The notion that hormesis is a widespread or important phenomenon in biological systems is not widely accepted.^[2]

The biochemical mechanisms by which hormesis works are not well understood. It is conjectured that low doses of toxins or other stressors might activate the repair mechanisms of the body. The repair process fixes not only the damage caused by the toxin, but also other low-level damage that might have accumulated before without triggering the repair mechanism.

History

German pharmacologist Hugo Schulz first described such a phenomenon in 1888 following his own observations that the growth of yeast could be stimulated by small doses of poisons. This was coupled with the work of German physician Rudolph Arndt, who studied animals given low doses of drugs, eventually giving rise to the Arndt-Schulz rule.^[1] Arndt's advocacy of homeopathy contributed to the rule's diminished credibility in the 1920s and 1930s.^[1] The term "hormesis" was coined and used for the first time in a scientific paper by C.M. Southam and J. Ehrlich in 1943 in the journal: Phytopathology, volume 33, pp. 517–541. Recently, Edward Calabrese has revived the hormesis theory through his research on peppermint plants.^{[3] [4]}

Examples of hormesis

There is an extensive body of research that purports to demonstrate a variety of hormetic effects.

Most drugs are toxic when ingested in large quantities. A quantative measure of this fact is called the therapeutic index. Their beneficial action at correct dosage is not considered an example of hormesis.

Physical exercise

Individuals with low levels of physical activity are at risk for high levels of oxidative stress, as are individuals engaged in highly intensive exercise programs; however individuals engaged in moderately intensive, regular exercise experience lower levels of oxidative stress. High levels of oxidative stress have been linked by some with the increased incidence of a variety of diseases^[5] , It has been claimed that this relationship, characterized by positive effects at an intermediate dose of the stressor (exercise), is characteristic of hormesis^[6]. However, it is important to point out that there is evidence that the oxidative stress associated with intensive exercise may have long term health benefits. This would imply that oxidative stress, itself, provides an example of hormesis (see section on Mitochondrial hormesis), but physical exercise does not.^[7]

Alcohol

Main articles: Alcohol consumption and health, Alcohol and cancer, and Alcohol and cardiovascular disease

Alcoholic beverages are believed to be hormetic in preventing heart disease and stroke,^[8] although the benefits of light drinking may have been exaggerated.^[9]

Methylmercury and mallard eggs

In 2010, a paper published in the journal Environmental Toxicology & Chemistry showed that low doses of methylmercury, a potent neurotoxic pollutant, improved the hatching rate of mallard eggs.^[10] The author of the study, Gary Heinz, who led the study for the U.S. Geological Survey at the Patuxent Wildlife Research Center in Beltsville, Md., stated that other explanations are possible. For instance, it is possible that the flock he studied might have harbored some low, subclinical infection and that mercury, well known to be antimicrobial, might have killed the infection that otherwise hurt reproduction in the untreated birds.^[11]

Hormetic effects in aging

One of the areas where the concept of hormesis has been explored extensively with respect to its applicability is aging.^[12][13] Since the basic survival capacity of any biological system depends on its homeodynamic (homeostatic) ability, biogerontologists proposed that exposing cells and organisms to mild stress should result in the adaptive or hormetic response with various biological benefits. This idea has now gathered a large body of supportive evidence showing that repetitive mild stress exposure has anti-aging effects.^[14][15] Exercise is a paradigm for hormesis in this respect.^[15] Some of the mild stresses used for such studies on the application of hormesis in aging research and interventions are heat shock, irradiation, prooxidants, hypergravity and food restriction.^[15][16][17] Some other natural and synthetic molecules, such as celasterols from medicinal herbs and curcumin from the spice turmeric have also been found to have hormetic beneficial effects.^[18] Such compounds which bring about their health beneficial effects by stimulating or by modulating stress response pathways in cells have been termed "hormetins".^[14] Hormetic interventions have also been proposed at the clinical level,^[19] with a variety of stimuli, challenges and stressful actions, that aim to increase the dynamical complexity of the biological systems in humans.^[20]

Mitochondrial hormesis

Mitochondria are sometimes described as "cellular power plants" because they generate most of the cell's supply of adenosine triphosphate (ATP), a source of chemical energy. Reactive oxygen species (ROS) have been regarded as unwanted by-products of oxidative phosphorylation in mitochondria by the proponents of the free-radical theory of aging promoted by Denham Harman. The free-radical theory suggests that the use of compounds which inactivate ROS, such as so-called antioxidants, would lead to a reduction of oxidative stress and thereby produce an increase in lifespan. However in clinical trials the expected health-promoting effects of antioxidants were not found and results suggested that antioxidants may promote cancer in humans. Other studies have now shown that antioxidant supplements may be disease-promoting and increase mortality in humans.^[21]

ROS may perform an essential and potentially lifespan-promoting role as signaling molecules which transduce signals from the mitochondrial compartment to other compartments of the cell. Increased formation of reactive oxygen species (ROS) within the mitochondria may cause an adaptive reaction which produces increased stress resistance and a long-term reduction of oxidative stress. This kind of reverse effect of the response to ROS stress has been named mitochondrial hormesis or mitohormesis and is hypothesized to be responsible for the respective lifespan-extending and health-promoting capabilities of glucose restriction and physical exercise.^[21]

Hormesis may also 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. It was previously proposed on a hypothetical basis that such free radicals may induce an endogenous response culminating in increased defense capacity against exogenous radicals (and possibly other toxic compounds).^[22] Recent experimental evidence strongly suggests that this is indeed the case, and that such induction of endogenous free radical production extends life span of a model organism. Most importantly, this extension of life span is prevented by antioxidants, providing direct evidence that toxic radicals may mitohormetically exert life extending and health promoting effects.^[23] 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, with the free radicals acting as a signal within the cell to indicate which mitochondria are ready for destruction, as proposed by Nick Lane.^[24]

Another study on yeasts explains the underlying mechanism of the process that prevents cellular damage by reactive oxygen species.^[25] Whether this concept applies to humans remains to be shown, although recent epidemiological findings support the process of mitohormesis, and even suggest that some antioxidant supplements may increase disease prevalence in humans.^[26]

Controversy

Whether hormesis is common or important is controversial. At least one peer-reviewed article accepts the idea, claiming that over 600 substances show a U-shaped dose-response relationship. Calaberese and Baldwin wrote:

One percent (195 out of 20,285) of the published articles contained 668 dose-response relationships that met the entry criteria.^[27]

The idea that low dose effects may be (sometimes strikingly) different is accepted, but that the low dose effect is positive is questionable.

The hypothesis of hormesis has generated the most controversy when applied to ionizing radiation. This theory is called radiation hormesis. The commonly accepted model of dose response in radiobiology is the linear no-threshold model (LNT), which assumes a strictly linear dependence between the risk of radiation-induced adverse health effects and radiation dose.

The United States National Research Council (part of the National Academy of Sciences),^[28] the National Council on Radiation Protection and Measurements (a body commissioned by the United States Congress)^[29] and the United Nations Scientific Committee on the Effects of Ionizing Radiation (UNSCEAR) all agree that radiation hormesis is not clearly shown, nor clearly the rule for radiation doses.

A report commissioned by the French National Academy concluded that there is sufficient evidence for hormesis occurring at low doses and that LNT should be reconsidered as the methodology used to estimate risks from low level sources of radiation, like deep geological repositories for nuclear waste.^[30] On the other hand, the United States-based National Council on Radiation Protection and Measurements states that there is insufficient evidence for radiation hormesis and that radiation protection authorities should continue to apply the LNT model for purposes of risk estimation.^[31]

Policy consequences

Regulatory agencies such as the Environmental Protection Agency (EPA), the Food and Drug Administration (FDA), and the Nuclear Regulatory Commission (NRC) traditionally use a linear no-threshold model for carcinogens (including radiation). In the linear model, the assumption is that there is no dosage that has no risk of causing cancer. While this linear approach remains the default, with sufficient mechanistic evidence suggesting a non-linear dose-response, EPA allows for the derivation of a threshold dose (a.k.a reference dose) below which it is assumed that there is no risk for cancer.

While proponents of hormesis argue that changing to a hormesis model would likely change exposure standards for these toxicants in air, water, food and soil, making the standards less strict, other scientists point out that low dose stimulation can have extremely adverse effects. For example, research by Retha Newbold at the US National Institute of Environmental Health Sciences has shown that while relatively high doses of a xenobiotic estrogen, diethylstilbestrol, during fetal development cause weight loss in adulthood, extremely low doses cause grotesque obesity.^[32] Similarly, low doses of the phthalate DEHP cause increased allergic responses to allergens, while higher doses have no effect.^{[citation needed]} Low dose stimulation can have profoundly adverse consequences. Wider use of the hormesis model would affect how scientists design and conduct studies and the selection of models that estimate risk. In all likelihood, recognizing that low dose effects can't be predicted from high dose experiments would force a strengthening of public health standards, not their weakening, as hormesis proponents would argue.

See also

• Calorie restriction
• Michael Ristow
• Petkau effect
• Radiation hormesis
• Stochastic resonance

References

1. ^ ^{a b c} Kaiser Jocelyn (2003). "HORMESIS: Sipping From a Poisoned Chalice". Science 302 (5644): 376–379. doi:10.1126/science.302.5644.376. PMID 14563981. 
2. ^ Axelrod, Deborah, MD, et al. "'Hormesis'—An Inappropriate Extrapolation from the Specific to the Universal". International Journal of Occupational and Environmental Health, 2004;10:335–339. Retrieved 26-Feb-2006.
3. ^ Calabrese, Edward (2004). "Hormesis: a revolution in toxicology, risk assessment and medicine". EMBO 5: S37–S40. doi:10.1038/sj.embor.7400222. PMC 1299203. PMID 15459733. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1299203. 
4. ^ Bethell, Tom (2005). The Politically Incorrect Guide to Science. USA: Regnery Publishing. pp. 58–61. ISBN 089526031X. http://books.google.com/?id=xX4m7s7_4L0C&printsec=frontcover#PPA58,M1. 
5. ^ Zsolt Radak; Hae Y. Chung; Erika Koltai; Albert W. Taylor; Sataro Goto (January 2008). "Exercise, oxidative stress and hormesis". Ageing Research Reviews 7 (1): 34–42. doi:10.1016/j.arr.2007.04.004. PMID 17869589. 
6. ^ Op. cit.
7. ^ Zarse, Ristow M. (June 2010). "How increased oxidative stress promotes longevity and metabolic health: The concept of mitochondrial hormesis.". Exp Gerontol 45 (6): 140–8. PMID 20350594. 
8. ^ Cook, Ralph; Edward J. Calabrese (October 2006). "The Importance of Hormesis to Public Health". Environmental Health Perspectives. doi:10.1289/ehp.8606. Archived from the original on 2007-10-11. http://web.archive.org/web/20071011125206/http://www.ehponline.org/realfiles/members/2006/8606/8606.html. Retrieved 2007-03-24. 
9. ^ "International study questions health benefits of moderate drinking". http://www.eurekalert.org/pub_releases/2006-03/uoc--isq032706.php. 
10. ^ Heinz, G.H., et al. 2010. Enhanced Reproduction in Mallards Fed a Low Level of Methylmercury: An Apparent Case of Hormesis. Environmental Toxicology & Chemistry 29(March):650. DOI: 10.1002/etc.64
11. ^ Quoted in the article in Science News
12. ^ Eric Le Bourg and Suresh Rattan editors: Mild Stress and Healthy Aging: Applying hormesis in aging research and interventions, 2008 (ISBN 978-1-4020-6868-3)
13. ^ Rattan, S.I.S. Principles and practice of hormetic treatment of aging and age-related diseases. Human and Experimental Toxicology, 27: 151-154, 2008.
14. ^ ^{a b} Rattan, S.I.S. Hormesis in aging. Ageing Research Reviews, 7: 63-78, 2008.
15. ^ ^{a b c} Gems, David; Linda Partridge (2008-03-05). "Stress-Response Hormesis and Aging: "That which Does Not Kill Us Makes Us Stronger"". Cell Metabolism 7 (3): 200–203. doi:10.1016/j.cmet.2008.01.001. PMID 18316025. http://www.sciencedirect.com/science/article/B7MFH-4S03FX4-6/2/a1bb97b273bf727609b6eaa24894bb89. Retrieved 2008-04-03. 
16. ^ Le Bourg and Rattan editors: Mild Stress and Healthy Aging: Applying hormesis in aging research and interventions, 2008 (ISBN 978-1-4020-6868-3)
17. ^ Rattan S.I.S. (2008). "Hormesis in aging". Ageing Research Reviews 7 (1): 63–78. doi:10.1016/j.arr.2007.03.002. PMID 17964227. 
18. ^ Ali R.E., Rattan S.I.S. (2006). "Curcumin's biphasic hormetic response on proteasome activity and heat shock protein synthesis in human keratinocytes". Annals of the New York Academy of Sciences 1067: 394–399. Bibcode 2006NYASA1067..394A. doi:10.1196/annals.1354.056. PMID 16804017. 
19. ^ Marios Kyriazis 2005. Clinical anti-aging hormetic strategies. Rejuvenation Res. 8(2):96-100
20. ^ Kyriazis M (2003). "Practical applications of chaos theory to the modulation of human ageing: nature prefers chaos to regularity". Biogerontology 4 (2): 75–90. doi:10.1023/A:1023306419861. PMID 12766532. 
21. ^ ^{a b} Ristow, M. .; Zarse, K. . (2010). "How increased oxidative stress promotes longevity and metabolic health: the concept of mitochondrial hormesis (mitohormesis)". Experimental gerontology 45 (6): 410–418. doi:10.1016/j.exger.2010.03.014. PMID 20350594.  edit
22. ^ Tapia, PC (2006). "Sublethal mitochondrial stress with an attendant stoichiometric augmentation of reactive oxygen species may precipitate many of the beneficial alterations in cellular physiology produced by caloric restriction, intermittent fasting, exercise and dietary phytonutrients: "Mitohormesis" for health and vitality". Med Hypotheses. 66 (4): 832–43. doi:10.1016/j.mehy.2005.09.009. PMID 16242247. PubMed listing
23. ^ Schulz, Tim J.; Zarse, Kim; Voigt, Anja; Urban, Nadine; Birringer, Marc; Ristow, Michael (2007). "Glucose Restriction Extends Caenorhabditis elegans Life Span by Inducing Mitochondrial Respiration and Increasing Oxidative Stress". Cell Metabolism 6 (4): 280–293. doi:10.1016/j.cmet.2007.08.011. PMID 17908557.  abstract at journal website
24. ^ Lane, Nick (November 17, 2006). Power, Sex, Suicide: Mitochondria and the Meaning of Life. Oxford University Press. ISBN 0199205647. 
25. ^ Kelley R, Ideker T (March 30, 2009). Gibson, Greg. ed. "Genome-Wide Fitness and Expression Profiling Implicate Mga2 in Adaptation to Hydrogen Peroxide". PLoS Genet 5 (5): e1000488. doi:10.1371/journal.pgen.1000488. PMC 2676504. PMID 19503593. http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1000488. 
26. ^ Bjelakovic G, Nikolova D, Gluud L, Simonetti R, Gluud C (2007). "Mortality in Randomized Trials of Antioxidant Supplements for Primary and Secondary Prevention: Systematic Review and Meta-analysis". JAMA 297 (8): 842–57. doi:10.1001/jama.297.8.842. PMID 17327526. http://jama.ama-assn.org/cgi/content/abstract/297/8/842. 
27. ^ Calabrese EJ, Baldwin LA (Aug 2001). "The frequency of U-shaped dose responses in the toxicological literature". Toxicol Sci. 62 (2): 330–8. doi:10.1093/toxsci/62.2.330. PMID 11452146. 
28. ^ http://books.nap.edu/catalog/11340.html Health Risks from Exposure to Low Levels of Ionizing Radiation: BEIR VII Phase 2
29. ^ NCRP Store - Add Product to Cart
30. ^ André Aurengo; Dietrich Averbeck; André Bonnin; Bernard Le Guen; Roland Masse; Roger Monier; Maurice Tubiana; Alain-Jacques Valleron et al. (2005-03-30) (PDF). Dose-effect relationships and estimation of the carcinogenic effects of low doses of ionizing radiation. Académie des Sciences & Académie nationale de Médecine. http://www.radscihealth.org/rsh/Papers/FrenchAcadsFinal07_04_05.pdf. Retrieved 2008-03-27. 
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Further reading

Hormesis: A Revolution in Biology, Toxicology and Medicine., By Mark P. Mattson, Edward J. Calabrese (2009)

External links

• International Dose-Response Society