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.

Hormesis dose response.

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.