28 May 2019 Hormesis Part 1: Does Stress Make You Stronger?
How many times have you heard that “what doesn’t kill you makes you stronger”?
This philosophy isn’t uncommon, and there is some truth to it, but it can also be incredibly dangerous.
Recently, an equivalent concept by the name of “hormesis” has been gaining traction in the alternative health sphere.
Hormesis is the idea that a small amount of stress or damage causes our body to adapt in a way that allows us to become stronger and improves our health.
You may be surprised to hear that many popular treatments, supplements, and dietary paradigms, like ketogenic diets, intermittent fasting, resveratrol, fish oil and omega-3s, and cold thermogenesis or cryotherapy, are grounded in this idea of hormesis (in these contexts it may also be referred to as mitohormesis). And the benefits of more classic interventions, like caloric restriction and exercise, are also now being attributed to hormesis.
It’s often said that these diets or treatments can improve mitochondrial function, increase cellular repair, promote autophagy, stimulate mitochondrial biogenesis, and cause other supposedly beneficial effects. These “hormetic effects” are all part of our adaptation to the stress caused by these interventions and are considered to be responsible for their health benefits.
In other words, these interventions are known to cause stress, and it’s now being suggested that our adaptation to this stress is what makes these factors beneficial.
But, while hormesis sounds logical on the surface, as we dig deeper we’ll find that this concept is deeply flawed.
The Origins of Hormesis
Before we can determine whether the idea of hormesis is relevant to our physiology, we must first examine its origins and how it relates to stress and adaptation.
The idea of hormesis began with the suggestion that certain toxic agents (like ionizing radiation, methylmercury, and other poisons) triggered beneficial adaptive responses in low doses. In other words, the minor damage they caused would improve our body’s natural defenses.
And, this idea happened to be a convenient justification for the negligence of various industries, as Dr. Ray Peat has summarized:
“The idea that a little bit of something harmful is good for you was adopted by the petroleum, chemical and nuclear industries and their agents in government around 1950, and treated as a scientific concept, with the name ‘hormesis.’ When the public was starting to worry about the increased radioactivity of the environment because of nuclear bomb explosions, the US government was actively suppressing information on the increasing amount of environmental ionizing radiation, but they were even more active in promoting the idea that “small amounts” of radiation are harmless and even beneficial.” (1)
In addition to defending our exposure to small amounts of ionizing radiation, this idea has since been used to defend our exposure to low doses of pesticides, heavy metals like mercury and arsenic, toxic compounds in vaccines, chemotherapy drugs, endotoxin (also known as lipopolysaccharide or LPS), antinutrients and various polyphenols, and even cigarette smoke, among other things, by suggesting that not only are small amounts of these toxic factors not harmful, they’re actually beneficial due to the adaptive responses they cause (2, 3, 4, 5, 6, 7, 8).
According to this original definition of hormesis, the response to these toxic factors followed the curve shown below in Figure 1.
This curve represents the idea that at very small doses, these factors would create a beneficial response (the maximum response). Then at a certain dose, the NOAEL (meaning the no observed adverse effect level) would be reached, where the toxic factor supposedly has no net effect on the organism. Then, at any dose after the NOAEL, the toxic exposure would be harmful.
It’s important to note that the average dose used for the supposed hormetic effect (at the “maximum response”) is 5 times lower than the dose at the NOAEL (where there is no net effect on the organism), so we’re talking about extremely small doses of these toxic factors.
There are several issues with this original notion that I’ll touch on throughout this article, but one of the most important to note is that the “benefits” seen at these very low doses of toxic factors come at the cost of harm elsewhere (2, 3, 9).
Hormetic doses of dioxin (TCDD), for example, were shown to reduce cancer incidence in the pituitary, uterus, mammary glands, pancreas, and adrenal glands. But, the same dose increased cancer incidence in the liver, lung, tongue, and nasal turbinates (9). And hormetic doses of cadmium have been shown to cause non-statistically significant reductions in testicular tumors but also an increase in the incidence of prostate tumors (9).
These flaws aside, the concept of hormesis has undergone quite an expansion in recent decades that’s made its definition quite difficult to nail down.
Instead of referring only to the supposedly beneficial adaptations that result from the damage caused by very low doses of toxic environmental agents, the concept is now being applied to any factor that exhibits a biphasic (or triphasic) dose-response rather than a linear dose-response.
This includes any stimulus that follows normal or inverted J-shaped dose-response curves (like in Figure 1) or U-shaped curves, like the one depicted here:
In relation to hormesis, the J-shaped curve characterizes the idea that lower doses of a substance are beneficial while higher doses are harmful. And the U-shaped curve characterizes the idea that moderate amounts of a substance are beneficial, but too little or too much is harmful.
(Note: the effects can also be reversed if the curves are inverted.)
The conflation of these two mostly independent phenomena (the adaptive response to toxins and the biphasic or triphasic dose-response) has resulted in a 2nd definition of hormesis that’s no longer restricted to exposure to very low doses of toxins, and can instead be applied to virtually all environmental inputs.
This is because factors that follow these response curves are extremely common, including everything from exercise to sunlight exposure to vitamins and minerals. And, in accordance with the original definition of hormesis, researchers are attributing the effects of the factors following these dose-response curves to defensive adaptations in response to stress.
So, they’re suggesting that the benefits from exercise, ketogenic diets, caloric restriction, sunlight, cold or heat exposure, and even from essential nutrients like water, vitamins, and minerals, are due to the stress, or “hormetic effects,” they supposedly cause (4, 6, 7, 8, 10, 11, 12, 13).
And considering the original concept of hormesis, this isn’t such a stretch.
Those in favor of this idea suggest that the stress caused by these factors causes the body to adapt in a way that protects it from future stress. This then supposedly results in beneficial effects like DNA repair, antioxidant production, autophagy (the recycling of cellular components), increased lifespan, increased mitochondrial function, increased resistance to stress, and overall improved health.
To muddy the waters even further, other researchers are operating on a 3rd definition of hormesis, where they entirely ignore the stress component and determine hormetic factors solely based on the non-linear dose-response curves (13).
In this series of articles, I’ll be focusing on the 2nd of these 3 definitions, where the health benefits of all factors that follow these non-linear dose-response curves are attributed to the adaptive response to the stress they cause. This is the definition that’s most relevant and most commonly used to defend the use of various health-related hormetic interventions.
To summarize this definition succinctly, you could simply say that it’s the idea that small amounts of stress are beneficial to our health because they improve our body’s defenses, and that this stress is responsible for the health benefits of virtually all aspects of our environment.
(Note: The latter part of this definition isn’t agreed upon by all in favor of hormesis.)
Now in order to understand the flaws with this concept, we must explore the relationship between stress and adaptation.
Stress and Adaptation
Hans Selye’s work was pivotal in forming our understanding of stress and adaptation.
Selye recognized that all stimuli have unique, specific effects on our physiology. Exercise, for example, causes tension on our musculofascial system, while sunlight exposure causes vitamin D to be produced from cholesterol (among other things). But, Selye was the first to elucidate the idea that all stimuli also share a common or generalized effect.
This common or generalized effect occurs on the bioenergetic level. All stimuli increase the usage of energy to some degree, which is called the stressor effect. Additionally, stimuli can either encourage or inhibit the production of energy, which we’ll be diving into later on in this series.
(Note: By “energy” I’m referring to physiological energy produced from mitochondrial respiration, which I describe further in this article.)
Hans Selye also described our body’s response to stimuli, or adaptation. Our bodies are constantly adapting, to every stimulus they’re faced with, in order to best adjust to their environment. This adaptation is dependent on both the stimulus’s specific effects and energetic effects, as well as on our internal environment.
Let’s consider how we adapt to stimuli based on each of these effects.
Our adaptations to specific effects are unique to each stimulus.
If we’re exposed to sunlight, our skin darkens by increasing melanin production so we don’t burn as easily. If we exercise, the muscles we use will grow and our neuromuscular connections will strengthen, allowing our muscles to produce greater amounts of force. And if we’re exposed to high ambient temperatures, our blood volume increases so we can sweat more and cool ourselves easier.
Our adaptations to the bioenergetic effects of stimuli, on the other hand, are directly related to our energy balance, or the balance between our energy supply and energy demand.
Energy drives our health and is needed for us to do anything and everything. When we have an energy deficit, our body reacts with a generalized response called the stress response (or just “stress”), which is primarily characterized by the release of stress hormones. These stress hormones allow for energy to be produced to make up for the energy deficit, which allows us to continue to function.
(Note: It’s important to point out that this stress isn’t the same as “psychological stress,” which is an emotional response. However, this emotional response can actually be both caused by stress and a cause of stress, as I explained here.)
So, the increased usage of energy or the inhibition of energy production by any stimulus can cause an energy deficit, leading to stress.
Over time, in response to this energy deficit, our body adapts by reducing the energy it uses and produces in order to conserve fuel and promote survival, which better prepares us to handle future stress at the cost of slowing our high-level functions. This adaptation is driven by increases in stress hormones over time, which I detailed in this article.
If we instead have an energy surplus, we adapt by increasing the amount of energy we use, which improves the functioning of our brain, digestive system, immune system, and other high-level functions. Our body will also favor energy production in place of fuel conservation, which allows us to further improve these functions and increases the pool of energy that we can draw from when we experience minor stressors, which then reduces harmful adaptations.
In this way, you could consider these adaptations to be positive feedback loops, where greater energy availability further increases energy availability and reduced energy availability further reduces energy availability.
Because of these adaptive mechanisms, our body will always adapt to stress in a way that encourages the conservation of fuel and energy and subsequently reduces higher-level functions. However, we must also keep in mind that the amount of energy we have available to deal with the stressors will determine the extent of these adaptations.
So, when analyzing the effects of any stimulus, we must weigh the beneficial and harmful specific effects of the stimulus with its stress-promoting or stress-inhibiting bioenergetic effects.
We must also consider that, because energetic effects are common between all stimuli, the effects are cumulative. So, in order to determine the total stress on an organism, we must consider the bioenergetic inputs from all factors in its environment.
Hormesis and Adaptation
How does all this tie into hormesis?
Well, hormesis began by suggesting that the specific effects of certain toxic agents (like ionizing radiation, methylmercury, and other poisons) caused beneficial adaptive responses. In other words, the damage they caused improved our defenses.
Then, hormesis morphed into the idea that the stress-promoting effects of all factors (like fasting, exercise, vitamins, and water) cause beneficial adaptive responses.
Underlying both definitions is the idea that the adaptive defensive reactions caused by stress or damage improve our health and allow us to function optimally. But, while this may sound logical on the surface, it’s really a reductionistic mischaracterization of adaptation.
Part of this mischaracterization is due to a lack of understanding of bioenergetics and an assumption that excess energy is actually harmful. This isn’t uncommon thinking nowadays, as obesity is blamed on “overnutrition” or “excess energy,” even though it’s a condition characterized by a lack of energy, like all chronic diseases. (You can find out more about the relationship between fat loss and energy in these articles.)
As you read earlier in relation to adaptation, excess energy allows us to adapt to our environment in a way that improves our overall function. And on the opposite end of the spectrum, when we’re exposed to a stressful or energy-demanding environment, we adapt in the opposite way to best fit that environment.
That means that, rather than expending our energy on having a high-functioning, high-performance system, we use our energy to deal with the stressful environment that we’re faced with and conserve our fuel to prepare for future stress.
As Dr. Ray Peat has explained, “if the environments that the organism encounters are abundant in resources the organism will develop its capacity, tending to maximize its ability to interact constructively.” However, “defensive reactions that simply assure survival often degrade functioning of the individual” (1).
So, the entire adaptive model from which hormesis operates is flawed – adaptations to stress do improve our ability to handle stress, but this comes at the cost of degrading our overall functional capacity.
In this article we’ve set the stage for the 2nd part of this series, where we’ll dig into the research supporting hormesis and identify its major flaws. We’ll also take a look at the many misapplications that have resulted from this flawed research, including ketogenic diets, intermittent fasting, caloric restriction, and more. Lastly, we’ll explore why stress is inherently harmful, but why we may not want to avoid everything that causes stress.
- Peat, Ray, Dr. “From ‘heroic medicine’ to ‘hormesis’: First deny that harm is done” Ray Peat’s Newsletter, November 2017.
- Kaiser, Jocelyn. “Hormesis. Sipping from a poisoned chalice.” Science (New York, N.Y.), vol. 302, no. 5644, 2003, pp. 376–79. doi:10.1126/science.302.5644.376.
- Axelrod, Deborah, et al. “”Hormesis”–an inappropriate extrapolation from the specific to the universal.” International journal of occupational and environmental health, vol. 10, no. 3, 2004, pp. 335–39. doi:10.1179/oeh.2004.10.3.335.
- Gems, David, and Linda Partridge. “Stress-response hormesis and aging: “that which does not kill us makes us stronger.”” Cell metabolism, vol. 7, no. 3, 2008, pp. 200–03. doi:10.1016/j.cmet.2008.01.001.
- Mattson, Mark P. “Hormesis defined.” Ageing research reviews, vol. 7, no. 1, 2008, pp. 1–7. doi:10.1016/j.arr.2007.08.007.
- Mattson, Mark P. “Dietary factors, hormesis and health.” Ageing research reviews, vol. 7, no. 1, 2008, pp. 43–48. doi:10.1016/j.arr.2007.08.004.
- Rattan, Suresh I. S. “Hormesis in aging.” Ageing research reviews, vol. 7, no. 1, 2008, pp. 63–78. doi:10.1016/j.arr.2007.03.002.
- Hayes, Daniel P. “Nutritional hormesis and aging.” Dose-response : a publication of International Hormesis Society, vol. 8, no. 1, 2009, pp. 10–15. doi:10.2203/dose-response.09-012.Hayes.
- Thayer, Kristina A., et al. “Fundamental flaws of hormesis for public health decisions.” Environmental health perspectives, vol. 113, no. 10, 2005, pp. 1271–76. doi:10.1289/ehp.7811.
- Calabrese, Edward J., et al. “Biological stress response terminology: Integrating the concepts of adaptive response and preconditioning stress within a hormetic dose-response framework.” Toxicology and applied pharmacology, vol. 222, no. 1, 2007, pp. 122–28. doi:10.1016/j.taap.2007.02.015.
- Martucci, Morena, et al. “Mediterranean diet and inflammaging within the hormesis paradigm.” Nutrition reviews, vol. 75, no. 6, 2017, pp. 442–55. doi:10.1093/nutrit/nux013.
- Hayes, Daniel P. “Adverse effects of nutritional inadequacy and excess: a hormetic model.” The American journal of clinical nutrition, vol. 88, no. 2, 2008, 578S-581S. doi:10.1093/ajcn/88.2.578S.
- Hayes, D. P. “Nutritional hormesis.” European journal of clinical nutrition, vol. 61, no. 2, 2007, pp. 147–59. doi:10.1038/sj.ejcn.1602507.