Hormesis/Hormetism - getting stronger through stress exposure

Hormesis

Hormesis is a biological phenomenon whereby a beneficial effect (improved health, stress tolerance, growth or longevity) results from exposure to low doses of an agent that is otherwise toxic or lethal when given at higher doses. The philosophy of Hormetism, advocated in this blog, is based upon harnessing this biological phenomenon in a deliberate and systematic way in order to increase strength and resilience.

The plot below illustrates how hormetic compounds exhibit a characteristic biphasic or “inverted U” dose response curve, rather than an inhibitory effect which decreases linearly or at least continuously, but still remains inhibitory, as the dose becomes more dilute. A linear dose response, the so-called LNT or “linear no-threshold” model is assumed in conventional toxicology. But it turns out that much of the time, hormesis is better model than LNT. Take a close look at the plot: at a low dose, the response of the “toxic” or inhibitory agent actually becomes stimulatory or beneficial to the organism. Can this really be — can something that is harmful at a high dose be good for you at a low dose? The answer, surprisingly, is yes, and not just in an isolated few cases, but across a broad range of chemicals, energy sources, and other stressful agents. Let’s look at the evidence.

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Chemicals. Hormesis was first reported in a 1943 issue of Phytopathology by C. Southam and J. Ehrlich, who described an oak bark compound that promoted fungal growth at low doses but strongly inhibited growth at higher doses. The term derives from the Greek word “hormo”, meaning to excite or stimulate. Hormesis should not be confused with homeopathy, which purports to treat illnesses using levels of dilution so extreme that not even one molecule of the substance may be present, while positing that the absent homeopathic substance leaves a “memory trace” that somehow triggers a positive response in the organism. By contrast, hormesis has been subjected to extensive empirical confirmation.

Since Southam and Erlich’s paper, thousands of other examples of compounds exhibiting hormetic effects have been documented. Some of these are well-recognized components of our diet–including trace metals, alcohol and caffeine–recognized to be essential or healthful at low doses, but detrimental or toxic at high doses. Edward Calabrese, a toxicologist in the School of Public Health and Health Sciences at the University of Massachusetts, Amherst, has probably done more than anyone to document the hormetic effects of chemicals of many classes (reactive oxygen species, pro-oxidants, antagonists, mutagens) in a wide range of microbes, plants and animals.

Radiation. Moving beyond chemical hormesis, we enter more controversial waters. While it has long been known that high or moderate levels of ionizing or nuclear radiation are damaging or deadly, it would surprise many people to learn that exposure to low levels of radiation–for example background radiation levels seen at higher altitudes– may actually have beneficial effects. And yet, that is what the evidence increasingly shows. This includes studies documenting reduced rates of cancer and death for (a) industrial workers who handle low-level radioactive materials; (b) residents of high altitude regions such as Colorado; (c) people exposed to higher levels of natural radon gas; and (d) survivors of atomic blasts a who lived outside of the immediate blast areas.

Sunlight. Exposure to low or moderate doses of other lower-energy forms of radiation, including gamma-rays and UV-radiation, has been tied to health benefits. The documented connection between UV radiation and skin cancer has led to a general tendency in society to shun unprotected tanning and cover up with sunscreen when heading to the beach or ski slopes. However, there are strong indications that exposure to the sun, in low or moderate doses, has several benefits. Well-known is the fact that sunlight is one of the most effective ways to generate natural Vitamin D in the body; less well-known is that fact that sunlight can actually reduce the incidence of cancer, as reported in the Feb. 2, 2005 issue of the Journal of the National Cancer Institute.

Dioxin. Studies have even shown that one of the most infamous environmental toxins, dioxin, is beneficial at very low doses. Dioxin is a related to the Vietnam-era defoliant Agent Orange and is a known carcinogen. Dioxin contamination found in residential areas led to several highly publicized evacuations entire neighborhoods in Love Canal, New York and Times Beach, Missouri. According to the EPA, there is no “safe” level of dioxin. And yet in rats, low doses of dioxin have been shown to greatly reduce the incidence of tumors. Analysis of data from the National Institute of Occupational Safety and Health surprisingly reveals that plant workers exposed to low or moderate levels of dioxin had reduced incidence of many types of cancer. And molecular studies of how dioxin binds to DNA suggest that it can both induce and inhibit carcinogenesis, depending on the dose and the type of tissue involved. So the story does not appear to be as cut and dried as the EPA would have it.

Other stresses. Beyond chemicals and radiation, other biological stresses have been shown to have hormetic effects. Some of the more interesting of these hormetic stresses include: calorie restriction, cold temperature, heat shock, and hypergravity.

A common mechanism? Is there a common thread that explains how such a diverse range of biological insults–chemicals, radiation, temperature, gravity, and calorie restriction–can strengthen organisms, and explains why this phenomenon occurs across the world of microbes, plants and animals? The hormetic effect also appears to involve several seemingly independent physiological systems, including the endocrine and immune systems, tissue repair and growth mechanisms, and neural plasticity.

Homeostasis. What these systems have in common is that they are all adaptive “homeostatic” systems which help restore the organism to optimal functioning after “perturbations” by external stressors. The principle of homeostasis was first articulated over a hundred years ago by the physiologist Claude Bernard, and it has since been well documented in a broad range of biological systems. What is remarkable with hormesis, however, is that similar adaptations can occur to so many different stressors, and the adaptations can be significant and in many cases permanent or long-lasting. While well documented, we are just beginning to understand the common mechanisms underlying hormesis.

Anti-stress genes. Researchers at the University of Massachusetts have proposed that hormetic stresses work by inducing cellular adaptations brought on by activation of an “anti-stress” gene regulatory network. In their article “Hormesis and Adaptive Cellular Control Systems” in the journal Dose-Response, Melvin Anderson and others present evidence that hormetic stressors are first detected by molecular sensors, which activate “transcription factors” and upregulate the expression of a suite of anti-stress gene networks. These genes in turn activate a cascade of “homeostatic pathways”, i.e., adaptive responses which protect cells from stressful environments. One example is the activation of so-called “heat shock proteins” expressed by cells from bacteria to mammals as an adaptive response to heat stress, allowing the cell to resist heat denaturation of cellular proteins. These metabolic adaptations protect against toxicity to cells or organs, but require a significant increase in energy expenditure by the organism. Depending on the concentration and duration of exposure, the cell can shift from a normal functioning state, to an adaptive and stressed state at mild to intermediate exposures, or ultimately to an overt state of toxicity in the presence of an overwhelming concentration of stressors. If this model is correct, an accurate classification of the cell state could be directly used in risk assessments of various biological stresses.

Immunotherapy. It can be argued that the immune system is a hormetic system, in which the stressor is an antigen. Proliferation of immune cells in response to antigen exposure represents a hormetic adaptation. As with other hormetic phenomena, the dose of the antigen is critical, as described in a review by Calabresi. ( “Hormetic Dose-Response Relationships in Immunology”). This understanding underlies the principle of vaccination, which results in increased tolerance to foreign agents such as infectious viral agents. What is increasingly evident, and exciting, is that the principle of immune “tolerization” can be extended to stressors beyond infectious agents, to address conditions such as autoimmune conditions, allergies and asthma. Allergen immunotherapy works by introducing very low doses of an allergen and gradually increasing the dosage to build up tolerance. According to Dr. Linda Cox, chair of the Immunotherapy and Diagnostics Committee of the American College of Allergy, Asthma and Immunology (ACAAI), studies in Germany and the U.S. showed significantly improved cost effectiveness of allergen immunotherapy compared with conventional anti-allergy drugs in treating allergic rhinitis and asthma. I’ve posted a fuller discussion about the scientific basis for allergen immunotherapy in my article on Allergies and hormesis.

Progressive hormesis. In the literature, there is an implicit assumption that the threshold dose between the beneficial range and the detrimental range is fixed. So the research on hormesis attempts to characterize the threshold dose for each particular compound being studied relative to a class of organisms. The threshold dose is assumed to be constant–not only for a population but for an individual. But it is likely to vary among individuals within a population. And what if it is in fact not a static threshold, but a dynamic one? In that case, individuals could be trained to adapt to higher and higher levels of a stressor over time?

Certainly, this has already been explicitly acknowledged in one case described above, allergen immunotherapy, where tolerization results from progressively increasing the dose of the allergen. Another well-established example of progressive hormesis is weight-training. So long as one does not overtrain, it is generally expected that muscular strength can be significantly increased by progressively increasing the magnitude of the weights being lifted, allowing for adequate intervals of rest to allow adequate tissue repair and growth of muscle tissue.

Hormetism puts forward the thesis that progressive hormesis is a general phenomenon that applies to virtually any stressor. Following the principles of intensity, constraint, oscillation, and gradualism outlined on the first page of this website, it should be possible to increase strength and tolerance with respect to a wide, virtually unlimited range of challenges and stressors. It will be interesting to explore the diverse applications of this approach to strengthening.

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RedFox said:

Following the psychology thread How to make stress your friend I'm starting this one to explore the physiological side of strengthening through intermittent stress exposure.

http://gettingstronger.org/hormesis/

Hormesis

Radiation. Moving beyond chemical hormesis, we enter more controversial waters. While it has long been known that high or moderate levels of ionizing or nuclear radiation are damaging or deadly, it would surprise many people to learn that exposure to low levels of radiation–for example background radiation levels seen at higher altitudes– may actually have beneficial effects. And yet, that is what the evidence increasingly shows. This includes studies documenting reduced rates of cancer and death for (a) industrial workers who handle low-level radioactive materials; (b) residents of high altitude regions such as Colorado; (c) people exposed to higher levels of natural radon gas; and (d) survivors of atomic blasts a who lived outside of the immediate blast areas.

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RedFox said:

(d) survivors of atomic blasts a who lived outside of the immediate blast areas.

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Double Blasted
Monday, July 16, 2012

In early August of 1945, Tsutomu Yamaguchi had a run of the worst luck imaginable. A double blast of radiation left his future, and the future of his descendants, in doubt. In this short: an utterly amazing survival story that spans ... well, 4 billion years when you get down to it.

On the morning of August 6th, 1945, Tsutomu Yamaguchi was in Hiroshima on a work trip. He was walking to the office when the first atomic bomb was dropped about a mile away. He survived, and eventually managed to get himself onto a train back to his hometown ... Nagasaki. The very next morning, as he tried to convince his boss that a single bomb could destroy a whole city, the second bomb dropped. Sam Kean, whose latest book The Violinist's Thumb scrutinizes the mysteries of our genetic code, tells Jad and Robert the incredible story of what happened to Tsutomu, explains how gamma rays shred DNA, and helps us understand how Tsutomu sidestepped a thousand year curse.

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Jonathan said:

Incidentally, Yamaguchi lived to be around 90 years old despite his experiences. Perhaps this was hormesis in action?

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Radiation Hormesis Overview
[..]
RADIATION HORMESIS IN IMMUNITY AND AVERAGE LIFE-SPAN
A century ago, Shrader showed low doses of ionizing radiation activated the immune System.[3] When infected with diphtheria bacillus, guinea pigs previously exposed to x-rays showed no disease while unexposed controls died with diphtheria the following day. Increased immune competence leads to decreased infection, respiratory disease and cancer. These, in turn, increase reproductive performance and average life-span. Early studies showed that exposures to ionizing radiation prior to antigen administration induced increased production of antibodies and that the high titer remained longer than that of unexposed controls.[2] Shrader’s protocol of experimental infection of both radiation-exposed and control animals is most useful.
“Irradiation of the pregnant animals... and the fetuses in utero caused an astounding decrease of the mortality of the (virus) infected baby mice.”[4] Recent research on radiation hormesis in immunity has now been summarized.[5]

Average life-span is an important parameter for the health benefits of low-dose irradiation. Early results with the flour beetle, Tribolium confusum, showed the maximum life-span was obtained with exposures to x-rays of about 150 cGy/d.[2] These results were amply confirmed. Results of one experiment prompted health physicists to suggest the radiation limit for humans should be 15 rem (15 cSv), one tenth of the amount which increased average life-span 120% of controls in mice fed uranium, then called “tube dust” or “Manhattan dust.”[6] Since wartime secrecy permitted no publication of the details of these experiments, the report of Lorenz showing increased average life-span in mice (Figure 2), rats and Guinea pigs was
greeted with flawed interpretation and disbelief.[7] This graph exposes the misinterpretation to conclude that control mice have longer average life-spans than the exposed mice
when the median value was used instead of mean or average. The disbelief spread when major laboratories were misled by repeating the Lorenz protocols with specific pathogenfree
(SPF) animals. Since SPF animals have no pathogens to cause infection, controls lived as long as irradiated mice and no hormesis was found. Radiation hormesis in life-span is now well accepted by those who incorporate low doses into their protocols (Table 3). Much of this research stopped about 1945, when financial support shifted to studies of harm from excess radiation.
Many of the 1000 references in “Radiation Hormesis” came from reports on the effects of high doses of ionizing radiation in experimental animals.[8] Recent references involve only human data.[9] Hormesis consistently occurred only in the lowest doses tested. Major physiologic functions (Table 1) were benefited. Early studies illustrate the safety of low-dose irradiation for different parameters of reproduction.

RADIATION HORMESIS IN REPRODUCTION
Evidence for radiation hormesis in reproduction came as a surprise to investigators. In the study which inaugurated health physics regulations, rats fed uranium dust produced more young than controls.[6] Rats exposed to 2.5 Gy x-rays showed superovulation and superimplantation. [10] When compared with controls, sterility was reduced in humans and mice previously exposed to x-rays (Table 4).[11,12,13] Conversely, fecundity increased in lightly irradiated animals.[14] Muramatsu and associates found increased litter size (Figure 3) in a colony of gamma irradiated mice, p = 0.02. Brown reported gamma-ray irradiated rats (2 cGy/d) exhibited superior health and reproduction.[15] When compared with controls (Figure 4), females of the 12th continuously irradiated generation had 117% more litters, 157% increase in litter size, 172% increased total litter weight, 147% increased number of weaned pups, and 137% greater total weight of young weaned. Increased fecundity was confirmed (Figure 5) with colonies of 12-82 generations of irradiated rodents.[13,15,16]
In contrast with the genetic monsters predicted in atomic bomb victims, low doses of ionizing radiation reduced genetic abnormalities. When both parents were exposed to <40 cGy, babies born to Japanese bomb survivors had 30% fewer molecular mutations and 33% fewer chromosomal aberrations than controls.[17] Also, phenotypic abnormalities were significantly reduced in babies born of mothers who received <20 cGy (Figure 6).[18] Exposure of Japanese fathers to low-dose irradiation resulted in no significant effect on the occurrence of phenotypic abnormalities in their offspring.
[..]
Japanese atomic bomb victims are generally considered to provide the most reliable index for the effect of acute external radiation in humans. Those exposed to lowdose irradiation had a lower cancer death rate than controls (Table 7). For every ten thousand persons exposed to 1-1.9 cGy there were 3 fewer leukemia deaths and 50 fewer solid cancer deaths than in controls.[38]
Although leukemia mortality rates increase dramatically with doses exceeding the threshold, atom bomb survivors exposed to 5- 10 cSv had 5.5 fewer leukemia deaths per 10,000 persons than controls. Later studies confirm radiation hormesis in cancer mortality, leukemia mortality and average life-span of Japanese atomic bomb survivors.[17] Such results from atom bomb survivors negate the concept that all radiation is harmful.
Populations with unusual chronic exposures support the above results. Many generations exposed to relatively high levels of background radiation (compared with nonmedical exposures of 2 mGy/y for the US) show improved health.[20,21] This includes over 70,000 exposed (3.3 mGy/y) and 70,000 control (1.07 mGy/y) Chinese peasants,
several villages in Brazil (20-35 mGy/y), the “old ones” living in the mountains of Kerala (estimated to be 10 mGy/y), villages on the coasts of Kerala (4-13 mGy/y), and Ramasar, Iran (7-480 mGy/y).
A remarkable example of radiation hormesis in cancer mortality involves people in 1360 Taiwan homes built in 1982-3; in 1992 these were found to have 60Co contaminated steel beams.[39] Assuming occupancy of eight hours per day, the average exposures were estimated to be 0.5 cSv/y with 10% receiving >5 cSv/y. The yearly cancer death rate in Taiwan was 10.5 per 10,000 people, 157 cancer deaths in 15 years. In contrast, only four persons died with cancer in the 10,000 people living 15 years in contaminated homes. The SMR for total cancer mortality in this exposed population was 0.025, an extraordinarily low value.
Fallout from a hydrogen bomb at Bikini Island covered 23 Japanese fishermen in March 1954. Whole-body exposures from gamma rays were estimated to be 200-670 cGy.[40] All had radiation sickness. One died within eight months. One died 21 years later with liver cirrhosis. None died with cancer within 25 years of their exposure. The lesson learned here and at Chernobyl is that some radiation sickness can be cured by appropriate medical care.
The Chernobyl nuclear reactor explosion revealed the depth of misguided beliefs about low-dose irradiation. Fear of radiation caused over 100,000 deaths by abortions and
suicide.[41] The Nuclear Energy Agency concluded: “Nevertheless, the dose estimates generally accepted indicate that, with the exception of thyroid disease, it is unlikely that
the exposure would lead to discernible radiation effects in the general population.”[42] The incidence of childhood thyroid cancer increased; deaths from thyroid cancer did not increase. Of 800,000 workers involved in the cleanup, 31 died from radiation within the first four months.[42] During the first decade, no one exposed to less than 2 Gy died with cancer which could be attributed to radiation.

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Growth rings on a larch tree after the Tunguska impact. The increased diameter of each successive ring shows the growth of the tree in a year. This cut supports the hypothesis that growth increased after the Tunguska explosion. In 1908 a large astronomical body exploded above Tunguska, Siberia, Russia. The energy released was equivalent to around 1000 times that of the Hiroshima atomic-bomb. 60 million trees were destroyed by the explosion, and accelerated growth in those remaining is probably due to less competition for light and fertilisation from the ash of the destroyed trees.

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[..]The most spectacular phenomenon observed in all the Tunguska trees examined is their accelerated growth, usually starting from 1909 but sometimes from some years later. In the example, Fig. 1, we can see the ring widths after the blast increased on average by more than four times. This growth has only weakened in recent years, when the tree reached the respectable age of more than 150 years.
Up to today the cause of the anomalous growth is controversial. The fact that the markedly accelerated growth was observed not only in surviving trees, but also in younger trees germinated after the catastrophe has been interpreted as a proof of genetic mutations ascribed to a nuclear explosion. However, we have found no trace of a nuclear process by examining the radiocarbon abundance in the 1903-1916 tree rings of one of our wood samples[1]. {Hormesis/stress can come in many forms}
Some researchers have found correlations between the anomalous tree growth and the position of the trees. They have explained their findings by hypothesizing a scattered fertilization by a "meteoric dust" that encouraged growth in some places and not in others.{new 'resources' coupled with the stress?} Indeed, we found a ring width increase of 300-500 % for some trees and of only 20-30 % for others. These differences, however, did not correspond to the position of the trees but to the dimensions of the growth rings before the catastrophe. The trees that grew more slowly before 1908 have been more advantaged by the explosion, with respect to the others, so that the event had an averaging influence on the final tree dimensions.

The testimonies collected from surviving trees lead us to the conclusion [3] that the reason for accelerated tree growth seems to derive from the improved environmental conditions after the explosion: ash fertilization by charred trees, decreased competition for light, greater availability of minerals {and different minerals from the meteor?} due to the increased distance between trees, etc. The more favourable conditions were relatively more fruitful for trees that had been more oppressed before the catastrophe and also favoured younger trees born after the explosion. [..]

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RedFox said:

http://www.radpro.com/641luckey.pdf

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Features
Over 1000 references
Over 100 photos and nearly 100 figures
Radiation deficiency data
Chapter summaries
Information blanks
Speculative implications
Cancer mortality
Summary
Radiation Hormesis presents the only critical review of the effects of whole-body exposure to low doses of ionizing radiation in animals. This is a "must read" book for radiobiologists, health-conscious individuals, and serious environmentalists. Topics discussed include our radiation environment, radiation hormesis in cancer mortality, growth and development, reproduction and mutation, immunity, and cancer. Data is presented that indicates that low doses of ionizing radiation may actually be beneficial to human health. This information could invalidate the "zero thesis" and linear models used by most regulatory agencies. The implications regarding eliminating linear models and accepting radiation hormesis are also discussed.

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monotonic said:

I remember the C's saying that suffering activates DNA. Perhaps conscious suffering is a key to hormesis?

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Odyssey said:

monotonic said:

I remember the C's saying that suffering activates DNA. Perhaps conscious suffering is a key to hormesis?

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Perhaps not just conscious suffering but a strong will to survive coupled with the physical/psychological resources needed for survival as well.

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[..]Another theory, however, derives from something closer to the idea expressed by Emile Durkheim, writing in The Elementary Forms of the Religious Life, Part 2, that pain, when it does not occur naturally, creates communal bonds in part because "suffering creates exceptional strength." The willingness and ability to endure pain for some greater cause tells you something about yourself and your fellow sufferers. A club is more valuable to you if you and everyone else endured feats of extreme physical endurance to enter it.
[..]
Pain, he's found, seems to play a central role in a group experience in a way that a pleasurable or neutral bonding experience simply doesn't. "It's a part of everyday life and we often seek it out in a number of ways," Bastian told me. "We tend to overvalue pleasure, but pain is a central part of what it means to be human and what makes us happy." [..]
At the end of the study, Bastian asked each individual how much pain she had experienced, and how she felt about her fellow study participants. The students who had endured the icy water and wall squats had not only felt more pain but had perceived a stronger bond with their fellow sufferers. They felt more solidarity with them and more loyalty to them - and they felt strongly that the experiment had created unity. Those who had participated in the non-painful version of the experiment felt no such thing.

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