06 Jun Hormesis Part 2: Flawed Research and Harmful Misapplications (Including Ketogenic Diets, Intermittent Fasting, Calorie Restriction, and More)
This article is quite a bit longer and more complex than most of my articles. If that doesn’t sound like your cup of tea, check out my other articles here.
In Part 1 of this article series, we outlined the basics of hormesis and how it relates to stress and adaptation. In this article, we’re going to dig into the research supporting hormesis and identify its major flaws. We’ll also take a look at the many misapplications of this erroneous concept, including ketogenic diets, intermittent fasting, caloric restriction, and more.
Flaws In The Research
As I mentioned in Part 1 of this series, most of the research supporting the original view of hormesis was based on particular benefits seen in response to low doses of toxic chemicals. But when all the data was looked at, it was found that these “benefits” came at the cost of harm elsewhere.
There were several other issues with this earlier research, including various methodological issues, conflicting data from different studies, and conflating stimulation or adaptation with health benefits (1, 2, 3).
As for the newer definition of hormesis (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), there’s a plethora of research to dig into.
One of the most commonly cited areas of research in support of this version of hormesis is caloric restriction.
It’s known that caloric restriction causes stress, and it’s also known that caloric restriction increases lifespan. So, those in favor of hormesis suggest that the stress caused by caloric restriction must be responsible for the increases in lifespan.
However, it’s clear that the benefits of caloric restriction aren’t due to the stress caused by the restriction of calories and are rather due to the restriction of particular amino acids, the restriction of PUFA, and poor study design, as I explained in this article. The reduction in endotoxin production also plays a major role in the benefits of caloric restriction and is independent of the stress caused by this intervention (4).
There are also issues with the various organisms used to study effects on lifespan, and these issues confound much of the research on lifespan extension beyond caloric restriction.
C. elegans, for example, are worms that are often used for these studies, but the extension of lifespan seen in this organism is accomplished by shifts toward or entry into a hibernation state called dauer rather than improvements in health (5).
The dauer state is activated by stress, which could be caused by things like a lack of food (caloric restriction) or overcrowding, and results in several metabolic changes: fat becomes heavily favored as a fuel over glucose, the activity of the Krebs cycle and electron transport chain is substantially decreased, and the metabolic rate is largely reduced (5). In this state, C. elegans also has much greater stress resistance.
However, this state doesn’t represent a viable, healthy state in a normal environment:
“It is important to note that the increased reliance on these alternative pathways can often result in energetically crippled, albeit long-lived animals. Mitochondrial-based metabolism and the TCA cycle presumably evolved in large part because of the ability to produce the most ATP molecules per unit of nutrient consumed. Reducing an organism’s reliance on such pathways may allow a worm to survive for an extended period of time in the controlled laboratory environment but would probably place this animal at a significant disadvantage in the real world, where only the fastest and reproductively fittest survive.” (5)
In a little bit, we’ll see that these adaptations to stress in C. elegans also happen to be mirrored in us humans.
Other studies have noted various other differences between C. elegans and other species, including that they’re resistant to extraordinarily high levels of superoxide and exhibit unique lifespan extension in response to various toxins that isn’t seen in other species (6).
In other words, just because certain interventions extend lifespan in C. elegans doesn’t mean they improve the health of C. elegans or that they would improve the health of other organisms. In fact, the extreme metabolic impairment that accompanies this lifespan extension would suggest the opposite.
In addition to life extension, there are several other adaptations to stress that are considered to be beneficial and are cited in support of hormesis, including autophagy, mitophagy, mitochondrial biogenesis, uncoupling, and resistance to oxidative stress, among others.
And, the activation of many of the signals that lead to these adaptations are also considered to be beneficial, including AMPK, Nrf1 and Nrf2, sirtuins (SIRTs), PGC-1α, PPAR-α, PPAR-γ, nitric oxide, and others, as well as the increased secretion of stress hormones like adrenaline (epinephrine) and cortisol.
But to evaluate whether these effects are truly beneficial, we have to begin at the origin of the stress adaptation cascade: reactive oxygen species.
Reactive Oxygen Species and Adaptation
Reactive oxygen species, or ROS, are highly reactive molecules that are normally produced in small amounts in the mitochondria as a byproduct of energy production. The production of ROS is increased during stress and also as a direct result of various damaging factors, like radiation and lipid peroxides.
The increased production of ROS has historically been considered harmful, as it’s a primary cause of cellular damage. The downstream effects of ROS include damage to proteins, lipids, and DNA, which can lead to cell death and are implicated in virtually all chronic diseases.
However, the role of ROS in the adaptive response has been elucidated more recently and has shifted the general sentiment towards a more positive light.
It’s been shown that ROS are necessary for many of the signaling functions that allow for adaptation, which includes adaptive responses like uncoupling, autophagy, and mitochondrial biogenesis, as well as the activation of heat shock protein, apoptosis, JNK and other inflammatory pathways, hypoxia inducing factor (HIF), and others (6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19).
Simply put, ROS are integral to the adaptive process.
And, the adaptive processes stimulated by ROS production are vital to our health. So, it’s not surprising that dysfunction in these adaptive pathways is implicated in aging and various diseases.
For example, reductions or defects in autophagy have been implicated in obesity, type 2 diabetes, neurodegenerative diseases like Parkinson’s and Alzheimer’s, rheumatoid arthritis, cardiovascular disease, cancer, liver disease, and other degenerative conditions (20, 21, 22, 23, 24, 25, 26, 27, 28). And, lower levels of uncoupling are associated with decreased lifespans (29).
So, based on these findings it’s assumed that increasing the stimulation of these adaptive processes, like uncoupling, autophagy, and mitochondrial biogenesis, by increasing ROS production will reduce aging and degeneration.
This has led to the supposition that hormetic interventions like ketogenic diets, caloric restriction, and exercise, which increase ROS production and cause stress, are beneficial by causing these adaptive downstream effects.
In other words, the entire model of hormesis hinges on the idea that stimulating adaptive responses, typically by increasing ROS production, is beneficial.
But this is a textbook example of the reductionist view of adaptation I explained in Part 1 of this series.
There’s no denying that ROS stimulate adaptive defensive reactions to better deal with whatever challenge is presented to the organism. And, assuming continued stress, this adaptation is always going to be better than less adaptation or no adaptation at all because it better suits the organism to deal with exposure to these stressors.
But that doesn’t mean that stimulating the production of ROS and the downstream adaptive processes is inherently beneficial for the organism.
In fact, increased levels of ROS are seen in aging and degenerative conditions, suggesting that exposing ourselves to factors solely on the basis of increased ROS production and the stimulation of adaptive responses is misguided, to say the least (5, 13, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48).
And, considering that there are reductions or defects in the adaptive processes like autophagy and uncoupling in these conditions despite the increased levels of ROS, increasing the production of ROS via stress to improve these conditions certainly doesn’t make much sense.
To explore this concept further, let’s consider the energetic contexts when ROS may be produced.
Reactive Oxygen Species and Energy
ROS and The High Energy State
The first situation when ROS are produced beyond typical levels would be the high-energy state. This state is the result of uninhibited energy production, where mitochondrial respiration functions efficiently and rapidly. As ATP levels rise relative to ADP, electrons build up at the electron transport chain, which then increases the production of ROS (5, 49, 50).
This ROS production then stimulates processes like mitochondrial biogenesis and autophagy, which improve our capacity for energy production and act as cellular repair processes. In this context, these adaptive processes would positively contribute to the health of the organism as a whole.
Then, in order to stop the continual production of ROS (which we know can be damaging), uncoupling occurs, which drastically reduces the production of ROS and also typically reduces the production of ATP. In this case, the reduced production of ATP isn’t an issue considering that a high level of ATP is what led to the ROS production in the first place.
It’s also important to note that in this scenario, the high-energy state of the cell (which involves both high ATP and high CO2), is protective against the ROS produced, preventing damage from occurring (51, 52, 53, 54, 55, 56).
Now let’s consider another situation where ROS are produced: the low-energy stress state.
ROS and The Low-Energy Stress State
ROS may be produced in this state for several reasons. They may be produced as a direct effect of damaging factors such as radiation or lipid peroxides, or they may be produced due to the inhibition of the function of the electron transport chain (or energy production) by factors like endotoxin, nitric oxide, lipid peroxides, PUFA metabolites, resveratrol, methylmercury, hypoxia, excess lactate, or a high FADH2/NADH ratio (57, 58, 59, 13, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 12, 71, 72, 73, 74, 75, 76, 77, 78, 79).
(Note: A high FADH2/NADH ratio occurs during excessive fat oxidation, which occurs during low-carb or ketogenic diets and fasting/starvation, as I detailed in this article.)
And, ROS produced in this context have many of the same effects, in this case characterized as defensive reactions. They stimulate processes like mitochondrial biogenesis and autophagy/mitophagy, which improve the organism’s ability to deal with future stressors (13, 57, 60, 62, 76, 77, 78, 79). And they also cause uncoupling in order to stop the continual production of ROS from the electron transport chain and the resulting damage that would occur (70, 78, 80, 81, 82, 83).
But in this scenario, the cellular energy state is low due to both the inhibited electron transport chain function and the subsequent uncoupling. This leaves the cell susceptible to oxidative damage from the ROS produced and also stimulates the production of stress hormones in order to supply fuel to the cell and drive energy production (84, 85, 86). This stress hormone production is acknowledged by those in favor of hormesis and is even considered to play a role in the “beneficial” hormetic effects (78, 87, 88).
Additionally, this low-energy uncoupled state promotes the Warburg effect, which is seen in cancer cells (89, 90, 91). In this situation, ATP can’t be produced at the electron transport chain due to the uncoupling and therefore must be produced by glycolysis.
To summarize, ROS in the low-energy stress state cause the same mitochondrial biogenesis, autophagy, and uncoupling as ROS in the high-energy state. But, because of the lack of energy, the cell is susceptible to damage by these ROS and stress hormones are released to supply fuel and drive energy production.
These stress signals cause a cascade of anti-metabolic effects, such as the inhibition of thyroid, reproductive, immune, and digestive function, which I’ve described in this article. Altogether, these effects parallel the dauer hibernation state seen when C. elegans experience stressful environments, where the conservation of energy and improved stress tolerance come at the cost of function.
So, it’s clear that the effects of ROS production are dependent on the energetic context. And, adaptations to ROS produced in the high-energy state are beneficial whereas adaptations to ROS produced in the low-energy stress state result in a cascade of harmful effects.
In support of this idea, it’s been suggested that the decoupling of ATP production and ROS production, or the production of ROS without adequate ATP production (which would be the low-energy stress state), is responsible for neurodegenerative conditions (57, 58). Additionally, it’s been shown that ischemia/reperfusion injury, neuronal excitotoxicity, and necrosis are caused by high ROS and low ATP (92, 93, 94), and this low-energy, high ROS state is also seen in aging, hypoxia, and insulin resistance (30, 40, 43, 46, 51, 95, 96).
So, contrary to the ideas put forth by those in favor of hormesis, just because ROS production may result in beneficial adaptive effects does NOT mean that increasing ROS or its downstream adaptive effects, like autophagy and mitochondrial biogenesis, even in non-excess, is inherently beneficial! We must consider the mechanism behind the production of ROS – whether it’s driven by a high energy state or by inhibited respiration and/or direct damage – in order to determine the effects.
When considering the organism as a whole, ROS production in the low-energy stress state leads to the conservation of energy and reduced complexity, which is largely mediated by the stress hormones. And if this continues chronically, it results in the degenerative states characterized by elevated ROS and low energy.
So at best, the hormesis research suggests that stress builds tolerance to stress and that, rather than improving our health, this stress tolerance reduces our ability to function on a high level.
To quickly summarize, stressors and damage that drain the energy pool and increase ROS production result in adaptations that are NOT ideal for the long-term health of the organism.
But, none of this is to say that there aren’t beneficial effects from factors that cause stress.
Weighing Specific Effects and Stress: Exercise, Intermittent Fasting, and Low-Carb & Ketogenic Diets
Considering that every factor results in some amount of energy usage, meaning that everything is a potential stressor, the fact that there are beneficial effects from stressors really goes without saying. But, in order to provide contrast with the idea that the benefits of these factors are derived from adaptations to the stress they cause, let’s break down a few examples.
Hormesis and Exercise
First let’s consider exercise. There are, without a doubt, beneficial effects of exercise. And, of course, exercise is a stressor, as it requires energy and can therefore cause stress. But, does that mean the benefits of exercise are due to the stress it causes?
Those in favor of hormesis argue that this is the case – that the stress from exercise results in adaptations that account for its beneficial effects. And this is even common to hear from those in the fitness industry – they’ll say that damaging or stressing our muscles is what causes the beneficial adaptations that lead to improved health. But, there’s considerable evidence against this position.
First is that walking and other leisurely activity has been shown to be massively beneficial compared to being sedentary, which has been shown to be detrimental independent of periods of intense physical activity (97, 98, 99, 100, 101, 102). In other words, inactivity throughout the day has been shown to harm our health and even intensely stressful physical activity during isolated instances (like working out) doesn’t make up for this sedentarism.
Additionally, when compared to more intense exercise, the benefits of leisurely activity have been shown to be much greater in proportion to the amount of stress caused, suggesting that aspects other than stress are responsible for the benefits of light activity (97, 98).
Second is that the benefits from different types of exercise can vary while the amount of energy used is the same, as is shown in various isocaloric exercise interventions (103, 104, 105, 106, 107). This suggests that the specific effects of exercise, like putting tension on the musculofascial system, must account for at least some of the benefits of exercise rather than the energy expended and resulting stress caused.
Third is that muscle growth, or hypertrophy, is more tightly related to mechanical loading rather than muscular stress or damage (108). And, hypertrophy in response to greater stress and damage appears to differ from hypertrophy in response to greater muscular tension (109).
Stress and damage appear to cause greater sarcoplasmic hypertrophy, which is an increase in protein content of the sarcoplasm that doesn’t contribute as much to muscular strength. This hypertrophy represents increases in resources within the cell, which improves the muscle’s ability to handle future stress.
This is contrasted with myofibrillar hypertrophy, which is an increase in the amount of myofibrillar protein in the muscle cell. An increase in these structural components enhances muscular strength and occurs in response to greater muscular tension with less stress and damage.
All of this suggests that while exercise does cause stress that leads to adaptation, it’s the specific effects, rather than the stressor effects, that are responsible for its benefits.
As an aside, it’s also worth mentioning that neither type of muscle growth is inherently beneficial. When considering the organism as a whole, muscle is very energetically expensive. So, excessive muscle mass can waste energy that would better be used by other areas of the body (like the brain), and therefore isn’t always ideal for our health.
Hormesis and Intermittent Fasting
We can look at intermittent fasting as a second example for which hormesis is cited as the reason for its benefits.
Intermittent fasting often takes the form of eating only within an 8-hour window and fasting during the other 16 hours of the day. In other words, intermittent fasting is simply a lack of food for an extended period of time.
The most noteworthy effects of intermittent fasting are therefore twofold:
- Immense stress caused by an acute lack of food (110, 111), and
- A reduction in gut irritation, because if we aren’t eating any food then any gut irritation would be drastically reduced
This lack of gut irritation is certainly beneficial (although it can be accomplished through other, less-stressful means), whereas the stress caused by the lack of food is quite harmful. And the final outcome of intermittent fasting would be determined by weighing these two effects against each other.
However, these two effects are often conflated.
If someone is experiencing benefits from intermittent fasting, it likely means that the benefits of reducing gut irritation are outweighing the stress of not eating. This is relatively common, as gut irritation (and the production of endotoxin and other toxic factors that comes with it) is one of the most universal and damaging issues we face in our modern world and can therefore outweigh the stress caused by a lack of food.
Those in favor of hormesis, however, attribute the benefits of intermittent fasting to the stress itself rather than the beneficial reduction in gut irritation. But, it’s now been shown that the beneficial effects of caloric restriction are due to the decrease in gut irritation and endotoxin production, not the adaptations to the stress caused by a lack of food, and the same is likely true of fasting (4).
While it may go without saying, because of the stress caused by not eating, the benefits of reduced gut irritation would be better achieved by improving gut function and reducing the consumption of irritating, hard-to-digest foods rather than intermittent fasting.
(For a more in-depth exploration of the harmful effects of fasting, check out this article)
Hormesis and Low-Carb, Ketogenic, and Carnivore Diets
The same can be said for low-carb, ketogenic, and carnivore diets, which mimic the fasted state (also called the starvation state). Like fasting or starvation, these diets cause considerable amounts of stress (112, 113, 114; this is also explained more thoroughly in these articles). And under the guise of hormesis, this stress is considered to be responsible for the benefits seen.
But, like fasting, the benefits from these diets can largely be attributed to reductions in gut irritation rather than stress because many of the irritating, hard-to-digest foods that would lead to increased endotoxin production are carbohydrates, and these types of foods are avoided on these diets. This has been supported by recent evidence showing that the anti-seizure benefits of ketogenic diets are due entirely to their effect on the gut and rather than the stress they cause (115).
The examples detailed in this section have supported that it’s the specific effects of stimuli that are responsible for any health benefits seen, not stress or damage. And remember, because energy consumption is a universal phenomenon between all stimuli, if stress or damage were responsible for the benefits of these factors, then the argument would have to be made that the stress caused by any factor, including things like ionizing radiation, psychological stress, and heavy metal exposure, is beneficial.
This brings us to the final feature of hormesis that needs to be addressed: the U-shaped curve.
All You Need Is… Stress?
As I mentioned in Part 1 of this series, the definition of hormesis is expanding, and not for the better. Anything that follows a U-shaped dose-response, meaning that it can be harmful at a low dose, beneficial at a moderate dose, and harmful again at a high dose, is now considered to be hormetic.
By disguising the idea of hormesis behind the U-shaped curve, it’s allowed those in favor of hormesis to suggest that virtually all environmental factors are hormetic, meaning that the benefits of all factors are attributed to adaptations to the stress or damage they cause.
It’s reached the point where the benefits from things like essential vitamins and minerals (sodium, potassium, calcium, iron, copper, zinc, vitamins A, C, and E, etc.) and even water are considered to be a result of hormesis because they follow this U-shaped curve (88, 116, 117, 118, 119).
And there’s no question that many of these factors do fit the U-shaped dose-response:
- Exercising too little is harmful, a moderate amount of exercise is beneficial, and exercising too much is harmful
- Drinking too little water is harmful, drinking enough water is beneficial, and drinking too much water is harmful
- And consuming too little zinc is harmful, consuming enough zinc is beneficial, and consuming too much zinc is harmful
But just because they fit the U-shaped dose-response and can also cause stress does NOT mean that these factors are beneficial because they cause stress.
Yet that’s what’s being suggested.
Through its association with the U-shaped dose-response curve, hormesis has essentially become the idea that the only way to improve function is to cause stress or damage (which happens to support many modern medical interventions, industrial chemical and radiation exposure, and our terrible food supply and farming practices).
And, quite frankly, the definition had to expand in this way in order for hormesis to appear to be a viable concept. If it’s recognized that the benefits of factors that follow the “hormetic” U-shaped dose-response aren’t due to the stress they cause, it would have to be acknowledged that effects other than stress are responsible for the benefits of our environmental inputs, and eventually, that stress itself is harmful.
So instead, we’re left with the ridiculous notion that stress is the only way to improve health and function.
But this is utter nonsense! To suggest that these factors are hormetic would mean that in their ideal, most beneficial doses, they cause stress which leads to adaptations that account for their benefits.
I don’t know about you, but to me, suggesting that the proper amounts of essential nutrients like water and vitamins and minerals are beneficial because they cause stress, rather than because they supply a vital nutrient that’s required for us to properly function, is simply ridiculous, if not entirely illogical.
They even suggest that intellectual activities, such as those examined in this study, are beneficial for the brain due to their hormetic effects (120). But, the study they cited shows that increased leisure activity and cognitive stimulation, such as reading magazines and playing bingo or card games, are beneficial for the brain.
To suggest that these activities are stressful enough to be hormetic is nonsensical, especially when these are the same people saying that caloric restriction and substantial amounts of exercise, which are both considerably stressful, fall in the same hormetic dose range. By this same reasoning, simply standing in place or typing on a keyboard would be stressful enough to be hormetic, so why would we need exercise anyway?
As you can see, by the logic of this new definition of hormesis, literally any environmental factor that we adapt to, which is all environmental factors, is hormetic.
They’ve muddied the waters so much that “hormesis” has become synonymous with “adaptation,” allowing them to suggest that because water and cognitive stimulation are beneficial, ionizing radiation, dangerous heavy metals, and other toxic factors must be as well.
This absurdity leads us to the final major flaw in the concept of hormesis, and specifically its relationship with the U-shaped curve: stress is cumulative.
As I explained in Part 1, stress is a universal response to an energy deficit. And, because all stressors draw from the same energy supply, the stressor effect, or the amount of energy used, is cumulative.
So, in order to determine the amount of stress we’re experiencing, we have to add up the energy used by all stressors we’re exposed to and weigh this against our energy supply. For example, the energy required for any physical activity would be added to the energy required for any mental activity, as well as the energy used for immune system function, breathing, digesting, and every other stressor we encounter.
While this may seem obvious, it actually poses a major problem for those in favor of hormesis.
Increasing exposure to hormetic factors is suggested as the answer for preventing or reversing degeneration, chronic disease, and obesity. And many common health recommendations, like caloric restriction, exercise, intermittent fasting, ketogenic and low-carb diets, and cold exposure, fall into this category of hormetic intervention.
But, in order for increasing exposure to hormetic factors to be the answer for preventing or reversing degeneration, chronic disease, and obesity, the people with these conditions would have to be experiencing too little stress!
And this is actually the argument that’s being made – it’s being suggested that because of our ample food supply, sedentarism, and general ease of life, we’re experiencing too little stress.
Now this obviously can’t be thought through too clearly if the same people who are suggesting that reading magazines or drinking ideal amounts of water are stressful enough to be hormetic are also suggesting that our 40+ hour workweeks, poor quality food, constant exposure to unnatural EMFs and chemical insults, and various other stressors are not stressful enough.
Along with all this is the lack of awareness that these factors, as well as a lack of sunlight, lack of sleep, lack of social interaction, and many other aspects of our modern lives, actually inhibit our ability to produce energy, so our capacity for handling increased energy demands is drastically reduced.
In fact, considering our capacity to handle stressors, we’re likely experiencing more stress now than we ever have before.
(Note: If you’re thinking that the presence of obesity means that we have excess energy and a lack of stress, take a look at these articles.)
All of this then has to make you wonder… if the dose-response follows a U-shaped curve, all of the stress and damage is cumulative, and every single factor in our environment causes us harm in order to maintain our health through protective adaptations, how could we ever have too little stress?
And if we instead go along with the assumption that we have too little stress despite the excessive number of stressors we consistently face, how could it ever be possible to be on the “too much stress” side of the curve?
As one researcher pointed out specifically in regard to chemical stressors:
“… Calabrese maintains that maximal low-dose hormetic response (stimulation) occurs on average at a dose fivefold below the “no observed adverse effect level” (NOAEL). If this were the case, then simultaneous exposure to five or more compounds that are equally potent in eliciting a given response, each at a level one fifth of the NOAEL, would be enough to move an organism from the low-dose potentially “beneficial” range, to the range where adverse effects are expected. Given that residues of hundreds of chemicals can be measured in humans,31-35 many affecting the same tissues and fluctuating in concentration over the course of a lifetime, trying to titrate exposure to achieve a relatively narrow hormetic range is untenable.” (2)
And that’s only considering the toxic chemicals we’re exposed to, not the various “new” hormetic factors like water, exercise, and micronutrients.
Suffice it to say that when all these factors are accounted for, hormesis certainly fails as a scientific concept.
In fact, considering that adaptations to stress and damage don’t improve our health, stress and damage are cumulative, and that the benefits of environmental stimuli are due to their specific effects rather than the stress they cause, hormesis would be best characterized as an extreme misrepresentation of the interaction between the organism and its environment.
The idea that environmental factors are beneficial because of the stress or damage they cause is an incredibly dangerous premise, especially when it comes to regulating our exposure to toxic chemicals and radiation, and even more so when the cumulative effects of these exposures are considered.
As we’ve already acknowledged, stress is NOT beneficial and low doses of stress or damage do NOT result in adaptive benefits to the organism as a whole.
Now, does this mean we should try to avoid anything that causes stress?
No, not at all.
In fact, we can’t!
All aspects of our environment can cause stress because they all demand energy. And we don’t need to avoid a stressor like exercise simply due to the stress it causes because its other beneficial effects can outweigh this stress.
So how do we determine which stressors we should avoid?
Selye described that our adaptation to a stimulus is dependent on the stimulus’s specific effects, stressor effects, and our internal environment. And, he explained that excessive amounts of stress lead to all sorts of symptoms and conditions.
This is because energy is the driver of our health and is needed for us to do anything and everything. So, the balance between the energy we produce and the energy we use is of utmost importance.
Any time our energy demands outweigh our energy supply, it encourages adaptations that allow us to make up for the energy deficit. While helpful in the short-term, these adaptations come at the cost of reducing our structural complexity and function, as these are both energy-dependent. They also result in adaptations that allow us to conserve energy to handle future stressors, which further reduce our structural complexity and function.
This energy deficiency and the resulting reduction in complexity and function underlies virtually all the negative health symptoms we may experience, from fatigue to a lack of libido to an inability to concentrate to constant hunger and cravings.
Excessive amounts of energy usage, or an excessive energy demand, is therefore extremely detrimental. And, optimizing energy production, or mitochondrial respiration, is the best way to increase our resistance and resilience to the stressors that we’ll inevitably experience.
So, exposing ourselves to factors with the least energy demand relative to their beneficial specific effects is ideal for our health. These specific effects would, on their deepest level, be measured by their ability to impact energy production.
In general, stressors that offer little benefit and are extremely energetically demanding or inhibiting, like ionizing radiation and endotoxin exposure, are best avoided, while other stressors that offer considerable benefit but can also be quite stressful, like exercise, are best used when they’re balanced with effective energy production.
If we were to evaluate the use of interventions like ketogenic diets, calorie restriction, or intermittent fasting through this lens, we’d see that they’re generally a terrible idea because they’re disastrous for energy production, which I’ve written about here.
As I mentioned earlier, there are potential benefits from these interventions that mostly stem from a lack of gut irritation, which would contribute towards improving energy production. But, these benefits can be attained in ways that don’t concurrently inhibit energy production, such as eating easily digestible foods and correcting gut function.
Along with these principles, it’s important to recognize our body’s natural drive for optimization and increased complexity. By providing it with adequate resources and minimal energy demands, it adapts by using increasing energy availability, allowing it to thrive and maximize its capabilities.
Dr. Ray Peat has effectively summated this idea in the following paragraph:
“It’s important to minimize “low level” stressors and injuries, and to optimize the protective factors, such as light, carbohydrate, thyroid hormone, carbon dioxide, and a sense of a meaningful future. A positively beneficial environment supports constructive, and reconstructive, processes in the body that can correct much of the damage done by bad aspects of the environment, at any previous stage of development (Katz, et al., 1982; Yang, et al., 2015; Griñan-Ferré, et al., 2016; Kentner, et al., 2016). All of the body’s tissues, including the brain, are subject to revision and reconstruction. The weight of the brain, and the thickness of the cortex can be increased by environmental enrichment (Díaz, 1988; Rosenzweig and Bennett, 1996; Schrott, 1997; Lehohla, et al., 2004).” (121, emphasis mine)
In other words, in nearly complete opposition to the intentional exposure to stressful experiences encouraged by hormesis, minimizing stress relative to energy production is the KEY to regeneration and health.
So, I’ll conclude this oversized article with some of the most effective “anti-hormetic” things we can do to minimize stress and maximize energy production:
- Eat a diet that’s composed of easily digestible foods, contains adequate nutrients (including sufficient calories and carbohydrates), and includes minimal amounts of toxins
- Expose ourselves to a stimulating environment with rich social interaction
- Stay active for the sake of enjoyment and movement rather than to expend as much energy as possible
- Minimize our exposure to toxic and harmful chemicals and radiation
- Minimize psychological stress
To dive deeper into these factors that drive energy production and minimize stress, be sure to sign up for the free health and energy balance mini-course below!
- Kaiser, Jocelyn (2003): Hormesis. Sipping from a poisoned chalice. In Science (New York, N.Y.) 302 (5644), pp. 376–379. DOI: 10.1126/science.302.5644.376.
- Axelrod, Deborah; Burns, Kathy; Davis, Devra; Larebeke, Nicolas von (2004): “Hormesis”–an inappropriate extrapolation from the specific to the universal. In International journal of occupational and environmental health 10 (3), pp. 335–339. DOI: 10.1179/oeh.2004.10.3.335.
- Calabrese, Edward J.; Bachmann, Kenneth A.; Bailer, A. John; Bolger, P. Michael; Borak, Jonathan; Cai, Lu et al. (2007): Biological stress response terminology: Integrating the concepts of adaptive response and preconditioning stress within a hormetic dose-response framework. In Toxicology and applied pharmacology 222 (1), pp. 122–128. DOI: 10.1016/j.taap.2007.02.015.
- Fabbiano, Salvatore, et al. “Functional Gut Microbiota Remodeling Contributes to the Caloric Restriction-Induced Metabolic Improvements.” Cell metabolism, vol. 28, no. 6, 2018, 907-921.e7. doi:10.1016/j.cmet.2018.08.005.
- Balaban, Robert S.; Nemoto, Shino; Finkel, Toren (2005): Mitochondria, oxidants, and aging. In Cell 120 (4), pp. 483–495. DOI: 10.1016/j.cell.2005.02.001.
- Sanz, Alberto (2016): Mitochondrial reactive oxygen species: Do they extend or shorten animal lifespan? In Biochimica et biophysica acta 1857 (8), pp. 1116–1126. DOI: 10.1016/j.bbabio.2016.03.018.
- Brookes, Paul S.; Levonen, Anna-Liisa; Shiva, Sruti; Sarti, Paolo; Darley-Usmar, Victor M. (2002): Mitochondria: regulators of signal transduction by reactive oxygen and nitrogen species. In Free radical biology & medicine 33 (6), pp. 755–764.
- Forman, Henry Jay; Maiorino, Matilde; Ursini, Fulvio (2010): Signaling functions of reactive oxygen species. In Biochemistry 49 (5), pp. 835–842. DOI: 10.1021/bi9020378.
- Schaar, Claire E.; Dues, Dylan J.; Spielbauer, Katie K.; Machiela, Emily; Cooper, Jason F.; Senchuk, Megan et al. (2015): Mitochondrial and cytoplasmic ROS have opposing effects on lifespan. In PLoS genetics 11 (2), e1004972. DOI: 10.1371/journal.pgen.1004972.
- Brookes, Paul S.; Yoon, Yisang; Robotham, James L.; Anders, M. W.; Sheu, Shey-Shing (2004): Calcium, ATP, and ROS: a mitochondrial love-hate triangle. In American journal of physiology. Cell physiology 287 (4), C817-33. DOI: 10.1152/ajpcell.00139.2004.
- Sauer, H.; Wartenberg, M.; Hescheler, J. (2001): Reactive oxygen species as intracellular messengers during cell growth and differentiation. In Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 11 (4), pp. 173–186. DOI: 10.1159/000047804.
- Chandel, N. S.; McClintock, D. S.; Feliciano, C. E.; Wood, T. M.; Melendez, J. A.; Rodriguez, A. M.; Schumacker, P. T. (2000): Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: a mechanism of O2 sensing. In The Journal of biological chemistry 275 (33), pp. 25130–25138. DOI: 10.1074/jbc.M001914200.
- Sena, Laura A.; Chandel, Navdeep S. (2012): Physiological roles of mitochondrial reactive oxygen species. In Molecular cell 48 (2), pp. 158–167. DOI: 10.1016/j.molcel.2012.09.025.
- Ježek, Jan; Cooper, Katrina F.; Strich, Randy (2018): Reactive Oxygen Species and Mitochondrial Dynamics: The Yin and Yang of Mitochondrial Dysfunction and Cancer Progression. In Antioxidants (Basel, Switzerland) 7 (1). DOI: 10.3390/antiox7010013.
- Ji, Li Li (2007): Antioxidant signaling in skeletal muscle: a brief review. In Experimental gerontology 42 (7), pp. 582–593. DOI: 10.1016/j.exger.2007.03.002.
- Gomez-Cabrera, Mari-Carmen; Borrás, Consuelo; Pallardó, Federico V.; Sastre, Juan; Ji, Li Li; Viña, Jose (2005): Decreasing xanthine oxidase-mediated oxidative stress prevents useful cellular adaptations to exercise in rats. In The Journal of physiology 567 (Pt 1), pp. 113–120. DOI: 10.1113/jphysiol.2004.080564.
- Echtay, Karim S.; Roussel, Damien; St-Pierre, Julie; Jekabsons, Mika B.; Cadenas, Susana; Stuart, Jeff A. et al. (2002): Superoxide activates mitochondrial uncoupling proteins. In Nature 415 (6867), pp. 96–99. DOI: 10.1038/415096a.
- Murphy, Michael P.; Echtay, Karim S.; Blaikie, Frances H.; Asin-Cayuela, Jordi; Cocheme, Helena M.; Green, Katherine et al. (2003): Superoxide activates uncoupling proteins by generating carbon-centered radicals and initiating lipid peroxidation: studies using a mitochondria-targeted spin trap derived from alpha-phenyl-N-tert-butylnitrone. In The Journal of biological chemistry 278 (49), pp. 48534–48545. DOI: 10.1074/jbc.M308529200.
- Andrews, Zane B.; Diano, Sabrina; Horvath, Tamas L. (2005): Mitochondrial uncoupling proteins in the CNS: in support of function and survival. In Nature reviews. Neuroscience 6 (11), pp. 829–840. DOI: 10.1038/nrn1767.
- Zhang, Kezhong (2018): “NO” to Autophagy: Fat Does the Trick for Diabetes. In Diabetes 67 (2), pp. 180–181. DOI: 10.2337/dbi17-0048.
- Bhattacharya, Debalina; Mukhopadhyay, Mainak; Bhattacharyya, Maitree; Karmakar, Parimal (2018): Is autophagy associated with diabetes mellitus and its complications? A review. In EXCLI journal 17, pp. 709–720. DOI: 10.17179/excli2018-1353.
- Yang, Jai-Sing; Lu, Chi-Cheng; Kuo, Sheng-Chu; Hsu, Yuan-Man; Tsai, Shih-Chang; Chen, Shih-Yin et al. (2017): Autophagy and its link to type II diabetes mellitus. In BioMedicine 7 (2), p. 8. DOI: 10.1051/bmdcn/2017070201.
- Yang, Zhen; Fujii, Hiroshi; Mohan, Shalini V.; Goronzy, Jorg J.; Weyand, Cornelia M. (2013): Phosphofructokinase deficiency impairs ATP generation, autophagy, and redox balance in rheumatoid arthritis T cells. In The Journal of experimental medicine 210 (10), pp. 2119–2134. DOI: 10.1084/jem.20130252.
- Jiang, Peidu; Mizushima, Noboru (2014): Autophagy and human diseases. In Cell research 24 (1), pp. 69–79. DOI: 10.1038/cr.2013.161.
- Levine, Beth; Kroemer, Guido (2008): Autophagy in the pathogenesis of disease. In Cell 132 (1), pp. 27–42. DOI: 10.1016/j.cell.2007.12.018.
- Jing, Kaipeng; Lim, Kyu (2012): Why is autophagy important in human diseases? In Experimental & molecular medicine 44 (2), pp. 69–72. DOI: 10.3858/emm.2012.44.2.028.
- Xie, Wei; Zhou, Jun (2018): Aberrant regulation of autophagy in mammalian diseases. In Biology letters 14 (1). DOI: 10.1098/rsbl.2017.0540.
- Glick, Danielle; Barth, Sandra; Macleod, Kay F. (2010): Autophagy: cellular and molecular mechanisms. In The Journal of pathology 221 (1), pp. 3–12. DOI: 10.1002/path.2697.
- Speakman, John R.; Talbot, Darren A.; Selman, Colin; Snart, Sam; McLaren, Jane S.; Redman, Paula et al. (2004): Uncoupled and surviving: individual mice with high metabolism have greater mitochondrial uncoupling and live longer. In Aging cell 3 (3), pp. 87–95. DOI: 10.1111/j.1474-9728.2004.00097.x.
- Boudina, Sihem; Sena, Sandra; Theobald, Heather; Sheng, Xiaoming; Wright, Jordan J.; Hu, Xia Xuan et al. (2007): Mitochondrial energetics in the heart in obesity-related diabetes: direct evidence for increased uncoupled respiration and activation of uncoupling proteins. In Diabetes 56 (10), pp. 2457–2466. DOI: 10.2337/db07-0481.
- Serrano, Faridis; Klann, Eric (2004): Reactive oxygen species and synaptic plasticity in the aging hippocampus. In Ageing research reviews 3 (4), pp. 431–443. DOI: 10.1016/j.arr.2004.05.002.
- Zhang, Jing; Perry, George; Smith, Mark A.; Robertson, David; Olson, Sandra J.; Graham, Doyle G.; Montine, Thomas J. (1999): Parkinson’s Disease Is Associated with Oxidative Damage to Cytoplasmic DNA and RNA in Substantia Nigra Neurons. In The American Journal of Pathology 154 (5), pp. 1423–1429. DOI: 10.1016/S0002-9440(10)65396-5.
- Anderson, Ethan J.; Lustig, Mary E.; Boyle, Kristen E.; Woodlief, Tracey L.; Kane, Daniel A.; Lin, Chien-Te et al. (2009): Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans. In The Journal of clinical investigation 119 (3), pp. 573–581. DOI: 10.1172/JCI37048.
- Szatrowski, T. P.; Nathan, C. F. (1991): Production of large amounts of hydrogen peroxide by human tumor cells. In Cancer research 51 (3), pp. 794–798.
- Valko, Marian; Leibfritz, Dieter; Moncol, Jan; Cronin, Mark T. D.; Mazur, Milan; Telser, Joshua (2007): Free radicals and antioxidants in normal physiological functions and human disease. In The international journal of biochemistry & cell biology 39 (1), pp. 44–84. DOI: 10.1016/j.biocel.2006.07.001.
- Giacco, Ferdinando; Brownlee, Michael (2010): Oxidative stress and diabetic complications. In Circulation research 107 (9), pp. 1058–1070. DOI: 10.1161/CIRCRESAHA.110.223545.
- Reuter, Simone; Gupta, Subash C.; Chaturvedi, Madan M.; Aggarwal, Bharat B. (2010): Oxidative stress, inflammation, and cancer: how are they linked? In Free radical biology & medicine 49 (11), pp. 1603–1616. DOI: 10.1016/j.freeradbiomed.2010.09.006.
- Bachschmid, Markus M.; Schildknecht, Stefan; Matsui, Reiko; Zee, Rebecca; Haeussler, Dagmar; Cohen, Richard A. et al. (2013): Vascular aging: chronic oxidative stress and impairment of redox signaling-consequences for vascular homeostasis and disease. In Annals of medicine 45 (1), pp. 17–36. DOI: 10.3109/07853890.2011.645498.
- Callaway, Danielle A.; Jiang, Jean X. (2015): Reactive oxygen species and oxidative stress in osteoclastogenesis, skeletal aging and bone diseases. In Journal of bone and mineral metabolism 33 (4), pp. 359–370. DOI: 10.1007/s00774-015-0656-4.
- Doria, Enrico; Buonocore, Daniela; Focarelli, Angela; Marzatico, Fulvio (2012): Relationship between human aging muscle and oxidative system pathway. In Oxidative medicine and cellular longevity 2012, p. 830257. DOI: 10.1155/2012/830257.
- Dias, Vera; Junn, Eunsung; Mouradian, M. Maral (2013): The role of oxidative stress in Parkinson’s disease. In Journal of Parkinson’s disease 3 (4), pp. 461–491. DOI: 10.3233/JPD-130230.
- Liu, Zhaohui; Li, Tianxia; Yang, Dejun; W. Smith, Wanli (2013): Curcumin protects against rotenone-induced neurotoxicity in cell and drosophila models of Parkinson’s disease. In APD 02 (01), pp. 18–27. DOI: 10.4236/apd.2013.21004.
- Lee, Hsin-Chen; Wei, Yau-Huei (2012): Mitochondria and aging. In Advances in experimental medicine and biology 942, pp. 311–327. DOI: 10.1007/978-94-007-2869-1_14.
- van Hameren, Gerben; Campbell, Graham; Deck, Marie; Berthelot, Jade; Chrast, Roman; Tricaud, Nicolas (2018): CMT disease 2A and demyelination decouple ATP and ROS production by axonal mitochondria.
- Gilgun-Sherki, Yossi; Melamed, Eldad; Offen, Daniel (2004): The role of oxidative stress in the pathogenesis of multiple sclerosis: the need for effective antioxidant therapy. In Journal of neurology 251 (3), pp. 261–268. DOI: 10.1007/s00415-004-0348-9.
- Shigenaga, M. K.; Hagen, T. M.; Ames, B. N. (1994): Oxidative damage and mitochondrial decay in aging. In Proceedings of the National Academy of Sciences of the United States of America 91 (23), pp. 10771–10778. DOI: 10.1073/pnas.91.23.10771.
- Wallace, D. C. (2001): Mouse models for mitochondrial disease. In American journal of medical genetics 106 (1), pp. 71–93. DOI: 10.1002/ajmg.1393.
- Couillard, A.; Prefaut, C. (2005): From muscle disuse to myopathy in COPD: potential contribution of oxidative stress. In The European respiratory journal 26 (4), pp. 703–719. DOI: 10.1183/09031936.05.00139904.
- Nicholls, David G. (2004): Mitochondrial membrane potential and aging. In Aging cell 3 (1), pp. 35–40. DOI: 10.1111/j.1474-9728.2003.00079.x.
- Salin, Karine; Auer, Sonya K.; Rey, Benjamin; Selman, Colin; Metcalfe, Neil B. (2015): Variation in the link between oxygen consumption and ATP production, and its relevance for animal performance. In Proceedings. Biological sciences 282 (1812), p. 20151028. DOI: 10.1098/rspb.2015.1028.
- Schütt, Florian; Aretz, Sebastian; Auffarth, Gerd U.; Kopitz, Jürgen (2012): Moderately reduced ATP levels promote oxidative stress and debilitate autophagic and phagocytic capacities in human RPE cells. In Investigative ophthalmology & visual science 53 (9), pp. 5354–5361. DOI: 10.1167/iovs.12-9845.
- Ghanta, Sailaja; Tsoyi, Konstantin; Liu, Xiaoli; Nakahira, Kiichi; Ith, Bonna; Coronata, Anna A. et al. (2017): Mesenchymal Stromal Cells Deficient in Autophagy Proteins Are Susceptible to Oxidative Injury and Mitochondrial Dysfunction. In American journal of respiratory cell and molecular biology 56 (3), pp. 300–309. DOI: 10.1165/rcmb.2016-0061OC.
- Miyoshi, Noriyuki; Oubrahim, Hammou; Chock, P. Boon; Stadtman, Earl R. (2006): Age-dependent cell death and the role of ATP in hydrogen peroxide-induced apoptosis and necrosis. In Proceedings of the National Academy of Sciences of the United States of America 103 (6), pp. 1727–1731. DOI: 10.1073/pnas.0510346103.
- Kogan, A. Kh; Grachev, S. V.; Eliseeva, S. V.; Bolevich, S. (1997): Uglekislyĭ gaz–universal’nyĭ ingibitor generatsii aktivnykh form kisloroda kletkami (k rasshifrovke odnoĭ zagadki évoliutsii). In Izvestiia Akademii nauk. Seriia biologicheskaia (2), pp. 204–217.
- Boljevic, S.; Kogan, A. H.; Gracev, S. V.; Jelisejeva, S. V.; Daniljak, I. G. (1996): Osobina ugljen dioksida da inhibise stvaranje aktivnih oblika kiseonika u ćelijama coveka i zivotinja i znacaj ove pojave u biologiji i medicini. In Vojnosanitetski pregled 53 (4), pp. 261–274.
- Veselá, A.; Wilhelm, J. (2002): The role of carbon dioxide in free radical reactions of the organism. In Physiological research 51 (4), pp. 335–339.
- Kawamura, Kasumi; Qi, Fei; Kobayashi, Junya (2018): Potential relationship between the biological effects of low-dose irradiation and mitochondrial ROS production. In Journal of radiation research 59 (suppl_2), ii91-ii97. DOI: 10.1093/jrr/rrx091.
- Marnett, L. (2001): Endogenous DNA damage and mutation. In Trends in Genetics 17 (4), pp. 214–221. DOI: 10.1016/S0168-9525(01)02239-9.
- Niedernhofer, Laura J.; Daniels, J. Scott; Rouzer, Carol A.; Greene, Rachel E.; Marnett, Lawrence J. (2003): Malondialdehyde, a product of lipid peroxidation, is mutagenic in human cells. In The Journal of biological chemistry 278 (33), pp. 31426–31433. DOI: 10.1074/jbc.M212549200.
- Vanasco, Virginia; Saez, Trinidad; Magnani, Natalia D.; Pereyra, Leonardo; Marchini, Timoteo; Corach, Alejandra et al. (2014): Cardiac mitochondrial biogenesis in endotoxemia is not accompanied by mitochondrial function recovery. In Free radical biology & medicine 77, pp. 1–9. DOI: 10.1016/j.freeradbiomed.2014.08.009.
- Taylor, Cormac T.; Moncada, Salvador (2010): Nitric oxide, cytochrome C oxidase, and the cellular response to hypoxia. In Arteriosclerosis, thrombosis, and vascular biology 30 (4), pp. 643–647. DOI: 10.1161/ATVBAHA.108.181628.
- Nisoli, Enzo; Carruba, Michele O. (2006): Nitric oxide and mitochondrial biogenesis. In Journal of cell science 119 (Pt 14), pp. 2855–2862. DOI: 10.1242/jcs.03062.
- Inoue, M.; Nishikawa, M.; Sato, E. F.; Ah-Mee, P.; Kashiba, M.; Takehara, Y.; Utsumi, K. (1999): Cross-talk of NO, superoxide and molecular oxygen, a majesty of aerobic life. In Free radical research 31 (4), pp. 251–260.
- Musatov, Andrej (2006): Contribution of peroxidized cardiolipin to inactivation of bovine heart cytochrome c oxidase. In Free radical biology & medicine 41 (2), pp. 238–246. DOI: 10.1016/j.freeradbiomed.2006.03.018.
- Pocernich, Chava B.; Butterfield, D. Allan (2003): Acrolein inhibits NADH-linked mitochondrial enzyme activity: implications for Alzheimer’s disease. In Neurotoxicity research 5 (7), pp. 515–520.
- Reed, Tanea; Perluigi, Marzia; Sultana, Rukhsana; Pierce, William M.; Klein, Jon B.; Turner, Delano M. et al. (2008): Redox proteomic identification of 4-hydroxy-2-nonenal-modified brain proteins in amnestic mild cognitive impairment: insight into the role of lipid peroxidation in the progression and pathogenesis of Alzheimer’s disease. In Neurobiology of disease 30 (1), pp. 107–120. DOI: 10.1016/j.nbd.2007.12.007.
- Cocco, T.; Di Paola, M.; Papa, S.; Lorusso, M. (1999): Arachidonic acid interaction with the mitochondrial electron transport chain promotes reactive oxygen species generation. In Free radical biology & medicine 27 (1-2), pp. 51–59.
- Madrigal-Perez, Luis Alberto; Ramos-Gomez, Minerva (2016): Resveratrol Inhibition of Cellular Respiration: New Paradigm for an Old Mechanism. In International journal of molecular sciences 17 (3), p. 368. DOI: 10.3390/ijms17030368.
- Gueguen, Naïg; Desquiret-Dumas, Valérie; Leman, Géraldine; Chupin, Stéphanie; Baron, Stéphanie; Nivet-Antoine, Valérie et al. (2015): Resveratrol Directly Binds to Mitochondrial Complex I and Increases Oxidative Stress in Brain Mitochondria of Aged Mice. In PloS one 10 (12), e0144290. DOI: 10.1371/journal.pone.0144290.
- Cambier, S.; Bénard, G.; Mesmer-Dudons, N.; Gonzalez, P.; Rossignol, R.; Brèthes, D.; Bourdineaud, J-P (2009): At environmental doses, dietary methylmercury inhibits mitochondrial energy metabolism in skeletal muscles of the zebra fish (Danio rerio). In The international journal of biochemistry & cell biology 41 (4), pp. 791–799. DOI: 10.1016/j.biocel.2008.08.008.
- Santore, Matthew T.; McClintock, David S.; Lee, Vivian Y.; Budinger, G. R. Scott; Chandel, Navdeep S. (2002): Anoxia-induced apoptosis occurs through a mitochondria-dependent pathway in lung epithelial cells. In American journal of physiology. Lung cellular and molecular physiology 282 (4), L727-34. DOI: 10.1152/ajplung.00281.2001.
- Selivanov, Vitaly A.; Votyakova, Tatyana V.; Zeak, Jennifer A.; Trucco, Massimo; Roca, Josep; Cascante, Marta (2009): Bistability of mitochondrial respiration underlies paradoxical reactive oxygen species generation induced by anoxia. In PLoS computational biology 5 (12), e1000619. DOI: 10.1371/journal.pcbi.1000619.
- Koziel, Agnieszka; Woyda-Ploszczyca, Andrzej; Kicinska, Anna; Jarmuszkiewicz, Wieslawa (2012): The influence of high glucose on the aerobic metabolism of endothelial EA.hy926 cells. In Pflugers Archiv : European journal of physiology 464 (6), pp. 657–669. DOI: 10.1007/s00424-012-1156-1.
- Speijer, Dave (2011): Oxygen radicals shaping evolution: why fatty acid catabolism leads to peroxisomes while neurons do without it: FADH₂/NADH flux ratios determining mitochondrial radical formation were crucial for the eukaryotic invention of peroxisomes and catabolic tissue differentiation. In BioEssays : news and reviews in molecular, cellular and developmental biology 33 (2), pp. 88–94. DOI: 10.1002/bies.201000097.
- Hue, Louis; Taegtmeyer, Heinrich (2009): The Randle cycle revisited: a new head for an old hat. In American journal of physiology. Endocrinology and metabolism 297 (3), E578-91. DOI: 10.1152/ajpendo.00093.2009.
- Menzies, Keir J.; Singh, Kaustabh; Saleem, Ayesha; Hood, David A. (2013): Sirtuin 1-mediated effects of exercise and resveratrol on mitochondrial biogenesis. In The Journal of biological chemistry 288 (10), pp. 6968–6979. DOI: 10.1074/jbc.M112.431155.
- Schönfeld, Peter; Reiser, Georg (2013): Why does brain metabolism not favor burning of fatty acids to provide energy? Reflections on disadvantages of the use of free fatty acids as fuel for brain. In Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 33 (10), pp. 1493–1499. DOI: 10.1038/jcbfm.2013.128.
- Miller, Vincent J.; Villamena, Frederick A.; Volek, Jeff S. (2018): Nutritional Ketosis and Mitohormesis: Potential Implications for Mitochondrial Function and Human Health. In Journal of Nutrition and Metabolism 2018. DOI: 10.1155/2018/5157645.
- Solaini, Giancarlo; Baracca, Alessandra; Lenaz, Giorgio; Sgarbi, Gianluca (2010): Hypoxia and mitochondrial oxidative metabolism. In Biochimica et biophysica acta 1797 (6-7), pp. 1171–1177. DOI: 10.1016/j.bbabio.2010.02.011.
- Anderson, Ethan J.; Yamazaki, Hanae; Neufer, P. Darrell (2007): Induction of endogenous uncoupling protein 3 suppresses mitochondrial oxidant emission during fatty acid-supported respiration. In The Journal of biological chemistry 282 (43), pp. 31257–31266. DOI: 10.1074/jbc.M706129200.
- Brand, Martin D.; Esteves, Telma C. (2005): Physiological functions of the mitochondrial uncoupling proteins UCP2 and UCP3. In Cell metabolism 2 (2), pp. 85–93. DOI: 10.1016/j.cmet.2005.06.002.
- Sullivan, Patrick G.; Rippy, Nancy A.; Dorenbos, Kristina; Concepcion, Rachele C.; Agarwal, Aakash K.; Rho, Jong M. (2004): The ketogenic diet increases mitochondrial uncoupling protein levels and activity. In Annals of neurology 55 (4), pp. 576–580. DOI: 10.1002/ana.20062.
- Bough, Kristopher J.; Wetherington, Jonathon; Hassel, Bjørnar; Pare, Jean Francois; Gawryluk, Jeremy W.; Greene, James G. et al. (2006): Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic diet. In Annals of neurology 60 (2), pp. 223–235. DOI: 10.1002/ana.20899.
- Laugero, Kevin D. (2004): Reinterpretation of Basal Glucocorticoid Feedback: Implications to Behavioral and Metabolic Disease. In Gerald Litwack (Ed.): Vitamins and hormones. Advances in research and applications., vol. 69. San Diego: Academic Press, an imprint of Elsevier Science (Vitamins & Hormones), pp. 1–29.
- Manoli, Irini; Alesci, Salvatore; Blackman, Marc R.; Su, Yan A.; Rennert, Owen M.; Chrousos, George P. (2007): Mitochondria as key components of the stress response. In Trends in endocrinology and metabolism: TEM 18 (5), pp. 190–198. DOI: 10.1016/j.tem.2007.04.004.
- Duclos, M.; Martin, C.; Malgat, M.; Mazat, J. P.; Chaouloff, F.; Mormède, P.; Letellier, T. (2001): Relationships between muscle mitochondrial metabolism and stress-induced corticosterone variations in rats. In Pflugers Archiv : European journal of physiology 443 (2), pp. 218–226. DOI: 10.1007/s004240100675.
- Masoro, Edward J. (2007): The role of hormesis in life extension by dietary restriction. In Interdisciplinary topics in gerontology 35, pp. 1–17. DOI: 10.1159/000096552.
- Martucci, Morena; Ostan, Rita; Biondi, Fiammetta; Bellavista, Elena; Fabbri, Cristina; Bertarelli, Claudia et al. (2017): Mediterranean diet and inflammaging within the hormesis paradigm. In Nutrition reviews 75 (6), pp. 442–455. DOI: 10.1093/nutrit/nux013.
- Samudio, Ismael; Fiegl, Michael; Andreeff, Michael (2009): Mitochondrial uncoupling and the Warburg effect: molecular basis for the reprogramming of cancer cell metabolism. In Cancer research 69 (6), pp. 2163–2166. DOI: 10.1158/0008-5472.CAN-08-3722.
- Valle, Adamo; Oliver, Jordi; Roca, Pilar (2010): Role of uncoupling proteins in cancer. In Cancers 2 (2), pp. 567–591. DOI: 10.3390/cancers2020567.
- Baffy, Gyorgy (2017): Mitochondrial uncoupling in cancer cells: Liabilities and opportunities. In Biochimica et biophysica acta. Bioenergetics 1858 (8), pp. 655–664. DOI: 10.1016/j.bbabio.2017.01.005.
- Granger, D. Neil; Kvietys, Peter R. (2015): Reperfusion injury and reactive oxygen species: The evolution of a concept. In Redox biology 6, pp. 524–551. DOI: 10.1016/j.redox.2015.08.020.
- Mattson, Mark P. (2003): Excitotoxic and Excitoprotective Mechanisms: Abundant Targets for the Prevention and Treatment of Neurodegenerative Disorders. In NMM 3 (2), pp. 65–94. DOI: 10.1385/NMM:3:2:65.
- Villena, Joan; Henriquez, Mauricio; Torres, Vicente; Moraga, Francisco; Díaz-Elizondo, Jessica; Arredondo, Cristian et al. (2008): Ceramide-induced formation of ROS and ATP depletion trigger necrosis in lymphoid cells. In Free radical biology & medicine 44 (6), pp. 1146–1160. DOI: 10.1016/j.freeradbiomed.2007.12.017.
- Short, Kevin R.; Bigelow, Maureen L.; Kahl, Jane; Singh, Ravinder; Coenen-Schimke, Jill; Raghavakaimal, Sreekumar; Nair, K. Sreekumaran (2005): Decline in skeletal muscle mitochondrial function with aging in humans. In Proceedings of the National Academy of Sciences of the United States of America 102 (15), pp. 5618–5623. DOI: 10.1073/pnas.0501559102.
- Mansouri, Abdellah; Muller, Florian L.; Liu, Yuhong; Ng, Rainer; Faulkner, John; Hamilton, Michelle et al. (2006): Alterations in mitochondrial function, hydrogen peroxide release and oxidative damage in mouse hind-limb skeletal muscle during aging. In Mechanisms of ageing and development 127 (3), pp. 298–306. DOI: 10.1016/j.mad.2005.11.004.
- Arem, Hannah; Moore, Steven C.; Patel, Alpa; Hartge, Patricia; Berrington de Gonzalez, Amy; Visvanathan, Kala et al. (2015): Leisure time physical activity and mortality: a detailed pooled analysis of the dose-response relationship. In JAMA internal medicine 175 (6), pp. 959–967. DOI: 10.1001/jamainternmed.2015.0533.
- Ma, Jing; Liu, Zhaomin; Ling, Wenhua (2003): Physical activity, diet and cardiovascular disease risks in Chinese women. In Public health nutrition 6 (2), pp. 139–146. DOI: 10.1079/PHN2002393.
- Biswas, Aviroop; Oh, Paul I.; Faulkner, Guy E.; Bajaj, Ravi R.; Silver, Michael A.; Mitchell, Marc S.; Alter, David A. (2015): Sedentary time and its association with risk for disease incidence, mortality, and hospitalization in adults: a systematic review and meta-analysis. In Annals of internal medicine 162 (2), pp. 123–132. DOI: 10.7326/M14-1651.
- Shiyovich, Arthur, et al. “Sitting and cardiovascular morbidity and mortality.” Harefuah, vol. 152, no. 1, 2013, 43-8, 58, 57.
- Dunstan, David W., et al. “Prolonged sitting: is it a distinct coronary heart disease risk factor?” Current opinion in cardiology, vol. 26, no. 5, 2011, pp. 412–19. doi:10.1097/HCO.0b013e3283496605.
- Katzmarzyk, Peter T., et al. “Sitting time and mortality from all causes, cardiovascular disease, and cancer.” Medicine and science in sports and exercise, vol. 41, no. 5, 2009, pp. 998–1005. doi:10.1249/MSS.0b013e3181930355.
- Schjerve, Inga E., et al. “Both aerobic endurance and strength training programmes improve cardiovascular health in obese adults.” Clinical science (London, England : 1979), vol. 115, no. 9, 2008, pp. 283–93. doi:10.1042/CS20070332.
- Wisløff, Ulrik, et al. “Superior cardiovascular effect of aerobic interval training versus moderate continuous training in heart failure patients: a randomized study.” Circulation, vol. 115, no. 24, 2007, pp. 3086–94. doi:10.1161/CIRCULATIONAHA.106.675041.
- Bweir, Salameh, et al. “Resistance exercise training lowers HbA1c more than aerobic training in adults with type 2 diabetes.” Diabetology & metabolic syndrome, vol. 1, 2009, p. 27. doi:10.1186/1758-5996-1-27.
- Bally, Lia, et al. “Metabolic and hormonal response to intermittent high-intensity and continuous moderate intensity exercise in individuals with type 1 diabetes: a randomised crossover study.” Diabetologia, vol. 59, no. 4, 2016, pp. 776–84. doi:10.1007/s00125-015-3854-7.
- Daussin, Frédéric N., et al. “Effect of interval versus continuous training on cardiorespiratory and mitochondrial functions: relationship to aerobic performance improvements in sedentary subjects.” American journal of physiology. Regulatory, integrative and comparative physiology, vol. 295, no. 1, 2008, R264-72. doi:10.1152/ajpregu.00875.2007.
- Chris Beardsley. What causes muscle growth? 2018, medium.com/@SandCResearch/what-causes-muscle-growth-c2744537ab0a.
- Greg Nuckols. Sarcoplasmic Hypertrophy: The Bros Were Probably Right: Does sarcoplasmic hypertrophy happen and, if so, what’s the effect on overall muscle growth? 2015, www.strongerbyscience.com/sarcoplasmic-vs-myofibrillar-hypertrophy/.
- Bergendahl, M., et al. “Fasting as a metabolic stress paradigm selectively amplifies cortisol secretory burst mass and delays the time of maximal nyctohemeral cortisol concentrations in healthy men.” The Journal of clinical endocrinology and metabolism, vol. 81, no. 2, 1996, pp. 692–99. doi:10.1210/jcem.81.2.8636290.
- Boelen, Anita, et al. “Fasting-induced changes in the hypothalamus-pituitary-thyroid axis.” Thyroid : official journal of the American Thyroid Association, vol. 18, no. 2, 2008, pp. 123–29. doi:10.1089/thy.2007.0253.
- Cox, Pete J., and Kieran Clarke. “Acute nutritional ketosis: implications for exercise performance and metabolism.” Extreme physiology & medicine, vol. 3, 2014, p. 17. doi:10.1186/2046-7648-3-17.
- Klein, S., and R. R. Wolfe. “Carbohydrate restriction regulates the adaptive response to fasting.” The American journal of physiology, vol. 262, 5 Pt 1, 1992, E631-6. doi:10.1152/ajpendo.1992.262.5.E631.
- McCue, Marshall D. “Starvation physiology: reviewing the different strategies animals use to survive a common challenge.” Comparative biochemistry and physiology. Part A, Molecular & integrative physiology, vol. 156, no. 1, 2010, pp. 1–18. doi:10.1016/j.cbpa.2010.01.002.
- Olson, Christine A., et al. “The Gut Microbiota Mediates the Anti-Seizure Effects of the Ketogenic Diet.” Cell, vol. 173, no. 7, 2018, 1728-1741.e13. doi:10.1016/j.cell.2018.04.027.
- Mattson, Mark P. “Hormesis defined.” Ageing research reviews, vol. 7, no. 1, 2008, pp. 1–7. doi:10.1016/j.arr.2007.08.007.
- Hayes, Daniel P. “Nutritional Hormesis and Aging.” Dose-Response, vol. 8, no. 1, 2009, pp. 10–15. doi:10.2203/dose-response.09-012.Hayes.
- 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.
- Scarmeas, Nikolaos, and Yaakov Stern. “Cognitive reserve and lifestyle.” Journal of clinical and experimental neuropsychology, vol. 25, no. 5, 2003, pp. 625–33. doi:10.1076/jcen.25.5.625.14576.
- Peat, Ray, Dr. “From ‘heroic medicine’ to ‘hormesis’: First deny that harm is done” Ray Peat’s Newsletter, November 2017.