Becoming Stress Proof: The History Of Stress With Hans Selye

Gregory Taper

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Becoming Stress Proof: The History of Stress With Hans Selye
http://www.dannyroddy.com/main/2012/6/2 ... selye.html

"Adaptability is probably the most distinctive characteristic of life."- Hans Selye

Everyone is experiencing some degree of stress all the time. Engaging in mental chess with a coworker, dealing with a serious illness, or deciding to the watch the 4-hour version of Gone With The Wind, are all examples of serious stressors that can be experienced daily.

While this sounds "all-bad," stress is the indispensable physiological ability to adapt when the production of energy is insufficient, and in the short-term, is protective.

However, after hour one of Gone With The Wind (or 20 minutes of the musical Evita) stress becomes pathogenic due to the hormones and inflammatory markers that play an important role in most all diseases.

It's hard to discuss stress without mentioning Hans Selye.

Selye helped coin the word stress in French (le stress), regularly displayed humility in his writing, and was a renegade endocrinologist that bet his entire career on the conventional views of stress being incorrect.

When compared to those who currently pontificate about the role of stress in disease, Selye's work is unique, in that he was an active participant in uncovering the numerous mechanisms behind the stress response: "Of course, only a small portion of this work was performed by our group in Montreal. Yet, I hope to give you a fairly accurate eyewitness account of its growth, for at least I can say: "I was there." I was there to watch as this field emerged from the unknown and as it went through the first stages of its development." - Hans Selye

A Non-Specific Syndrome That Isn't Worth Treating

Selye's concept of stress was formed by lectures he attended in 1925 as a medical student. As part of his curriculum, Selye was shown several patients in the earliest stages of various infectious diseases. The professor carefully pointed out that the patient looked and felt ill, had a coated tongue, digestive issues, aches and pains, was depressed, and had psoriasis.

However, the professor ignored the patients' symptoms explaining that they were "non-specific" and hence "of no use" when attempting to find a suitable drug for killing the germs "responsible" for making the patient ill.

The professor's course of identifying specific maladies to be treated by specific drugs was lost on Selye. Rather than accepting the close minded view towards the "non-specific" symptoms the patient was experiencing, Selye asked himself why a wide variety of disease states (measles, scarlet fever, influenza) shared the same "non-specific" symptoms of a number of toxic drugs, allergens, and non-infectious diseases.

This event left a profound impression on Selye and gave birth to "general adaptation syndrome" or GAS, which has also been referred to as "the stress syndrome" or "the syndrome of being sick."

General Adaptation Syndrome (GAS)

Selye described GAS as "general" because it brought upon a systemic defense phenomenon considered to be "adaptive" and "syndrome" because the individual manifestations varied depending on several different factors.

GAS could be elicited by exposing animals to toxins, adrenaline, insulin, extreme cold, extreme heat, x-rays, trauma (intense light or sound), hemorrhage, or inflicting pain or forced muscular exercise.

"We could find no noxious stimulus that did not elicit our syndrome." - Hans Selye

GAS can be broken up into three stages:

The Alarm Stage (Shock) - A generalized "call to arms" of the body's defensive mechanisms. No living organism can be maintained continuously in the alarm state. If the stress is great enough to be incompatible with life, then death occurs during the alarm reaction.

The Stage of Resistance - If an organism survives the alarm stage, what followed was a stage of adaptation, or resistance. In many ways the stage of resistance is the exact opposite of the alarm reaction. Whereas the alarm reaction is depleting, the stage of resistance is conserving.

The Stage of Exhaustion - Eventually, prolonged exposure to any stressor caused the loss of "adaptation energy." Symptomatology of the stage of exhaustion is strikingly similar to that of the initial alarm reaction causing premature aging and eventually death.

Criticisms of GAS

GAS was not accepted by Selye's peers, however:

"But. Selye. try to realize what you are doing before it is too late! You have now decided to spend your entire life studying the pharmacology of dirt!"

"Of course, he was right. Nobody could have expressed it more poignantly; that is why it hurt so much that I still remember the phrase after some 17 years. Only that to me the "pharmacology of dirt" - i.e, the response to non-specific damage as such - seemed the most promising subject in medicine." - Hans Selye

A frequent argument (that is still used today) is that "theories of everything" are bogus and that different diseases need to be treated differently.

Selye rejected this idea, while acknowledging that the idea of GAS, in the beginning, sounded just as incredible to him as it did to his critics:

"A priori we would be also inclined to think that if all our "diseases of adaptation" would have a single cause in the G-A-S, they should necessarily always occur, simultaneously in the same patient; everybody who is exposed to any stressor of sufficient intensity should develop them all. This is obviously not the case.

The same electricity can create motion, light, sound, heat, cold and innumerable combinations of these effects, depending upon whether it is conducted, selectively or in combination, to an electric motor, a light bulb, a bell, a stove, or a refrigerator.

For a savage who never heard of electricity it would be quite incredible that all these gadgets can be operated, singly or in any desired combination by regulating one force from a single switch board. To him this would seem just as incredible as it seemed to me at first, that diverse derailments of a single adaptation syndrome could call forth such vastly different manifestations of disease as those which I have enumerated in my previous lecture." - Hans Selye

Mystic Hippy Energy

The underlining factor that influenced the outcome of the animals ability to cope with any given stressor was dubbed "adaptation energy":

"Let us illustrate this point by an example. A rat is placed into a very cold room of, let us say, 2°c. It gradually learns how to conserve heat, by constriction of the peripheral vessels in the skin, an increase in basal metabolism and so forth. A priori I would have thought that the animal should now be able to live just as long in this cold chamber as at room temperature, assuming that we furnish the necessary calories to produce adequate amounts of heat. Yet, experience showed that continued exposure to cold or, as far as that goes, to any other stressor, sooner or later inexorably leads to a breakdown of the adaptive powers; that is, exhaustion of what has been called the adaptation energy." - Hans Selye

Energy?! Woah, woah, woaaaahhhh... I didn't sign on for this hippy ***t Roddy!

Look, there is nothing wrong with mystic hippy energy. I walked through Golden Gate Park today and was practically drowning in it. The bongos, the drum circles, the never ending stories of corporate espionage; hippy energy is clearly a part of the circle of life.

Selye's "adaptive energy," however, is something completely different:

"Furthermore. an animal highly adapted to one stressor agent (e.g., cold) loses much of its resistance and adaptability to other stressors (e.g.. drugs). We called this "crossed sensitization" and ascribed it to a consumption of adaptation energy, necessitated by exposure to the first stressor agent. Adaptation energy (whatever this may be) proved to be a finite quantity of which each organism has only a given amount. Presumably, genetic factors determine just how much of it is apportioned to each newborn individual. Yet, whatever the total quantity, it may be used up very slowly during a long, monotonously restful existence protected against every kind of exposure, or it may be consumed rapidly to maintain life under ever-changing conditions, which require extreme efforts of adaptation. It appeared to be something like an inherited fortune which could be spent sparingly over a long, quiet lifetime, or rapidly in generous. large sums to cover the exigencies of a vigorous and eventful existence." - Hans Selye

Stressor > Inherent [or Generative?] Adaptive Energy > Outcome Depends On Energy

So here we have a simple idea of stress as a tug-o-war between adaptive energy and any given stressor (allergen, environmental toxin, malnutrition, darkness, etc.).

Next week we'll explore adaptive energy and the role of the thyroid in the stress response.
 

Amazoniac

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@Zeus, jump to 13:14, maladaptation is actually just a correct adaptation to a bad environment. If they put both of those animals on ideal conditions, the marked (adapted) animal would probably have difficulty thriving. That's the challenge: to signal that the organism will no longer have to endure (and be prepared) for similar stresses.
Also the fact that whatever becomes available is being mobilized for repair, so the animal is in a constant debt after the massive stress if no temporary excesses are provided (one of the signals of good times).
 
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haidut

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@Zeus, jump to 13:14, maladaptation is actually just a correct adaptation to a bad environment. If they put both of those animals on ideal conditions, the marked (adapted) animal would probably have difficulty thriving. That's the challenge: to signal that the organism will no longer have to endure (and be prepared) for similar stresses. Also the fact that whatever becomes available is being mobilized for repair, so the animal is in a constant debt after the massive stress.

Thanks. As @tyw and I discussed in another thread, such signals of "bad times are over" seem to include testosterone (for males), progesterone, and possibly anti-serotonin drugs. The last one may need to be done in higher doses and/or chronically to reverse the signal.
Btw, when I said maladapted that's what I meant - adapting to bad environmental conditions and staying in that adaptation even if times change. I think the issue is that since adaptation (any adaptation) requires energy, if a hypothyroid organism is forced to adapt to bad conditions then it probably does not have enough energy to reverse that adaptation. Hence the need for thyroid, testosterone, progesterone, DHEA, serotonin blockade, etc as a way to alleviate that energetic deficit.
 

Amazoniac

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Is the thymus involuted on purpose? I suppose that a depleted organism just can't take constant inflammation, so it's better to desensitize itself than to exhaust.
It's interesting how when the body no longer can deal with a pathogen, it has to incorporate and live with it. And so it encapsulates the region to contain the problem so that it doesn't spread.
No wonder why weak metabolism is always linked to cancer. It's a state where toxins are beyond the capacity of detoxification.
 

haidut

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it has to incorporate and live with it. And so it encapsulates the region to contain the problem so that it doesn't spread

The thymus is probably involuted due to higher baseline cortisol and estrogen in low-energy states. As far as your comment, which I quoted - Peat said that anything foreign that the organism cannot get rid of is almost guaranteed to become cancer. So, maybe cancer is simply this - a foreign substance (or pathogen) of some sort that could not be expelled so it was embedded in the organism long ago. It was kept isolated while there were enough energy reserves but eventually cannot be contained and the organism starts to form an "ad-hoc" organ/tissue in that area, which is what Peat said cancer is - i.e. an ad-hoc organ/tissue created out of desperation and in a state of low energy reserves which prevents its proper differentiation. Supposedly, providing T3 to that ad-hoc organ/tissue induces proper differentiation.
Many people do not realize that the "revolutionary" stem cell treatments being promoted lately are just that - i.e. a form of cancer induction that is coaxed into differentiating with various chemicals or electrical signals. But since mainstream medicine does not know that well how to induce differentiation, there is a high chance the "treatment" will stay at the stage of cancerization. It's already happening, just Google for "stem cell treatment causes cancer".
 

Amazoniac

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The thymus is probably involuted due to higher baseline cortisol and estrogen in low-energy states. As far as your comment, which I quoted - Peat said that anything foreign that the organism cannot get rid of is almost guaranteed to become cancer. So, maybe cancer is simply this - a foreign substance (or pathogen) of some sort that could not be expelled so it was embedded in the organism long ago. It was kept isolated while there were enough energy reserves but eventually cannot be contained and the organism starts to form an "ad-hoc" organ/tissue in that area, which is what Peat said cancer is - i.e. an ad-hoc organ/tissue created out of desperation and in a state of low energy reserves which prevents its proper differentiation. Supposedly, providing T3 to that ad-hoc organ/tissue induces proper differentiation.
Many people do not realize that the "revolutionary" stem cell treatments being promoted lately are just that - i.e. a form of cancer induction that is coaxed into differentiating with various chemicals or electrical signals. But since mainstream medicine does not know that well how to induce differentiation, there is a high chance the "treatment" will stay at the stage of cancerization. It's already happening, just Google for "stem cell treatment causes cancer".
The final stage of decancerization is usually marked by fever, isn't it? It's almost like what's seen in a refeeding syndrome, where everything is being ordered, and the mess is finally being exposed and the body has to dispose it.
 

Amazoniac

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There you have it, from Stress in health and disease:

Syntoxic and Catatoxic Responses
"The biochemical analysis of the stress syndrome showed that homeostasis depends mainly upon two types of reactions: syntoxic (from the Greek syn or together) and catatoxic (from the Greek cata or against). Apparently, to resist different stressors the organism can regulate its own reactions through chemical messengers and nervous stimuli that either pacify or incite to fight. Syntoxic stimuli act as tissue tranquilizers, creating a state of passive tolerance that permits a kind of symbiosis, or peaceful coexistence, with aggressors. The catatoxic agents cause chemical changes (mainly through the production of hepatic microsomal enzymes) that lead to an active attack upon the pathogen, usually by accelerating its metabolic degradation.
Presumably, in the course of evolution the body learned to defend itself against all kinds of aggressors (whether arising in the organism or the environment) through mechanisms that help it tolerate the aggressor (syntoxic) or destroy it (catatoxic). Among the most effective syntoxic hormones are the glucocorticoids.
It is not immediately evident why it should be advantageous to inhibit inflammation or interfere with the rejection of foreign tissues, since both phenomena are essentially useful defense reactions. The main purpose of inflammation is to localize irritants (for example, microbes) by putting a barricade of inflammatory tissue around them to prevent their spread into the blood, which could lead to sepsis and even death. The suppression of this basic defense reaction is an advantage, however, when a foreign agent is in itself innocuous and causes trouble only by inciting inflammation. In such cases, inflammation itself is what we experience as a disease. Thus, in many patients who suffer from hay fever or extreme inflammatory swelling after an insect sting, suppression of defensive inflammation is essentially a cure, because the invading stressor agent is not in itself dangerous or likely to spread and kill. In the case of grafts, it may even be lifesaving.
At this point it is useful to distinguish between direct and indirect pathogens. Direct pathogens cause disease regardless of the body's reaction, whereas indirect pathogens cause damage only because they provoke exaggerated defensive responses. If a man accidentally exposes his hand to a strong acid, alkali or boiling water, damage will occur regardless of his reactions, because these are all direct pathogens. They would damage even the hand of a dead man, who obviously could not put up any defense reactions. Most common inflammatory irritants, including allergens, are essentially indirect pathogens: they cause disease only through the purposeless defense reactions that they stimulate.
Immunologic reactions, which lead to the destruction of microbes, grafts and other foreign tissues, undoubtedly developed during evolution as useful defensive mechanisms against potentially dangerous foreign materials. When the attack against the foreign agent is unnecessary or even harmful—as in the case of many allergens, heart transplants, and so on—man can improve upon the wisdom of Nature by suppressing this hostility. When the aggressor is dangerous, the defensive reaction should not be suppressed but if possible increased beyond the normal level, which can be achieved, for example, by catatoxic substances that carry the chemical message to the tissues to destroy the invaders even more vigorously than would normally be the case."

The Concept of Heterostasis
"Natural homeostatic mechanisms are usually sufficient to maintain a normal state of resistance; however, when the organism is faced with unusually heavy demands, ordinary homeostasis is not enough. The "thermostat of defense" must be raised to a heightened level. For this process, I proposed the term heterostasis (from the Greek heteros or other) as the establishment of a new steady state by treatment with agents that stimulate the physiologic adaptive mechanisms through the development of normally dormant defensive tissue reactions. Both in homeostasis and in heterostasis, the milieu interieur participates actively.
We can stimulate the production of natural protective agents by treatment with chemicals that augment the induction of catatoxic or syntoxic enzymes, or by immunization with bacterial products (for example, vaccination) that increase the body's manufacture of serologic antibodies to combat infections.
In homeostatic defense the potential pathogen (which threatens the fixity of the milieu interieur) automatically activates usually adequate catatoxic or syntoxic mechanisms; when these do burtlanthespecial not suffice, such natural catatoxic or syntoxic agents can also be administered readymade by the physician. Heterostasis depends upon treatment with artificial remedies that have no direct curative action, but which can precipitate the production of unusually high amounts of the body's own natural catatoxic or syntoxic agents so as to achieve fixity of the milieu interieury despite abnormally high demands that could not be met without outside help."

"When you meet a helpless drunk who showers you with insults but is obviously quite unable to do you any harm, nothing will happen if you take a syntoxic attitude—go past and ignore him. However, if you respond catatoxically and fight, or even only prepare to fight, the consequences may be tragic. You will discharge catecholamines that increase blood pressure and pulse rate, while your whole nervous system becomes alarmed and tense in anticipation of combat. If you happen to be a coronary candidate, the result may be a fatal brain hemorrhage or coronary accident. In this case, who is the murderer? The drunk didn't even touch you. This is biologic suicide! Death was caused by choosing the wrong reaction. If, on the other hand, the man who showers you with insults is a homicidal maniac with a dagger in his hand, evidently determined to kill you, you must take an aggressive catatoxic attitude. You must try to disarm him, even at the calculated risk of injury to yourself from the physical accompaniments of the alarm reaction in preparation for a fight. Contrary to common opinion, it is clear that Nature does not always know best, because on both the cellular and the interpersonal level, we do not always recognize what is and what is not worth fighting for."
 

Amazoniac

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So, Zeus, you know all this stuff yet you mentioned the possibility of one day selling your company to focus on writing books. Are you aware of the effects of such comment in our thymuses? Is it on purpose to later release a supplement that regenerates it? Is this the bi-winning mindset?
 

haidut

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So, Zeus, you know all this stuff yet you mentioned the possibility of one day selling your company to focus on writing books. Are you aware of the effects of such comment in our thymuses? Is it on purpose to later release a supplement that regenerates it? Is this the bi-winning mindset?

I may have been misunderstood :):
I don't want to sell the company. What I meant is that if I am to write books, having the company as well would be a major drawback and may doom the books as they would be labelled as simply a marketing gimmick. For now, and the foreseeable future, I am a product man not a book man. There is also something refreshing in working with physical objects. Doing nothing but reading and writing activates the serotonergic system. Even Peat spends one day a week without reading/talking and simply painting.
So, tell your thymus not to worry :):
 

Wagner83

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For some reason I found that interesting :
Biomineralization changes with food supply confer juvenile scallops (Argopecten purpuratus) resistance to ocean acidification. - PubMed - NCBI

Biomineralization changes with food supply confer juvenile scallops (Argopecten purpuratus) resistance to ocean acidification.
Ramajo L, et al. Glob Chang Biol. 2016.

Abstract

Future ocean acidification (OA) will affect physiological traits of marine species, with calcifying species being particularly vulnerable. As OA entails high energy demands, particularly during the rapid juvenile growth phase, food supply may play a key role in the response of marine organisms to OA. We experimentally evaluated the role of food supply in modulating physiological responses and biomineralization processes in juveniles of the Chilean scallop, Argopecten purpuratus, that were exposed to control (pH ~ 8.0) and low pH (pH ~ 7.6) conditions using three food supply treatments (high, intermediate, and low). We found that pH and food levels had additive effects on the physiological response of the juvenile scallops. Metabolic rates, shell growth, net calcification, and ingestion rates increased significantly at low pH conditions, independent of food. These physiological responses increased significantly in organisms exposed to intermediate and high levels of food supply. Hence, food supply seems to play a major role modulating organismal response by providing the energetic means to bolster the physiological response of OA stress. On the contrary, the relative expression of chitin synthase, a functional molecule for biomineralization, increased significantly in scallops exposed to low food supply and low pH, which resulted in a thicker periostracum enriched with chitin polysaccharides. Under reduced food and low pH conditions, the adaptive organismal response was to trade-off growth for the expression of biomineralization molecules and altering of the organic composition of shell periostracum, suggesting that the future performance of these calcifiers will depend on the trajectories of both OA and food supply. Thus, incorporating a suite of traits and multiple stressors in future studies of the adaptive organismal response may provide key insights on OA impacts on marine calcifiers.​
 

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Good Stress, Bad Stress and Oxidative Stress: Insights from Anticipatory Cortisol Reactivity

"When the principles of system robustness (Kitano, 2007) are applied to biological stress systems, robustness theory suggests that a heightened response to stress may help the body optimize performance to frequently encountered stressors. This may occur during chronic stress. In animal models, chronic stress exposure reorganizes neural networks regulating neuroendocrine function, providing an anatomical basis for more excitable cortisol responses to stress (Miklos and Kovacs, 2012). Hence, we propose that “anticipatory” cortisol reactivity (i.e., increases during psychological anticipation of the stressor) may be an important marker of a central nervous system that is “primed” for heightened stress-reactivity. Chronically stressed individuals may develop a heightened tendency to anticipate stress and mount a rapid cortisol response, which could increase vulnerability to oxidative stress and accelerate biological aging (Drabant et al., 2011; O'Donovan et al., 2012; Tomiyama et al., 2012)."

"The stress individuals experience as they anticipate a future event arises from their emotional and cognitive representations of what they believe or fear they will experience, rather than what they actually experience during the event. Moreover, some evidence suggests that chronic stress exposure may change the morphology of the brain regions that regulate neuroendocrine activity, promoting increased excitability of CRH neurons during stress (Miklos and Kovacs, 2012). Hence, chronic stress may predispose individuals to anticipate stress before the event occurs and mount a stronger corresponding cortisol response. These data, building upon previous findings in this sample (O'Donovan et al., 2012), underscore the important role of stress anticipation in relation to accelerated biological aging."

"Chronic stress-related alterations in biomarkers are often interpreted as a manifestation of “wear and tear” on the body or allostatic load (McEwen, 2004), as though the system were a rubber band that lost elasticity. However, an alternative and nonexclusive interpretation is that these changes may represent not so much a loss of resources, but a reallocation. Chronic stress reorganizes the structure of the central nervous system, providing an anatomical basis for changes in the dynamics (e.g., anticipatory reactivity) of stress hormones (Miklos and Kovacs, 2012). These changes may constitute an “intended” optimization of neuroendocrine system function, which has unfortunate “side effects”– i.e., the optimization increases short-term capacity for efficient responses to stress, while increasing long-term vulnerability to age-related disease. Seen from this light, heightened cortisol reactivity may not be a dysfunction or failure of the system per se, but an adaptation to cope with a demanding environment, which may have short term benefits to survival but longer term adverse consequences for healthy aging."

"Certain types of physiological stress, such as periodic exercise, are known to promote long-term decreases in circulating indicators of oxidative damage, apparently due to upregulation of antioxidant and other cytoprotective mechanisms (Radak et al., 2005). While purely speculative, it is conceivable that low-to-moderate episodic psychological stress exposure could improve psychobiological resilience to oxidative damage in a manner similar to exercise."
 

Amazoniac

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After hamster's post..

- Adrenal Gland Enlargement in Major Depression: A Computed Tomographic Study

upload_2019-7-27_20-1-44.png


upload_2019-7-27_20-4-46.png
 

Goobz

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Good Stress, Bad Stress and Oxidative Stress: Insights from Anticipatory Cortisol Reactivity

"When the principles of system robustness (Kitano, 2007) are applied to biological stress systems, robustness theory suggests that a heightened response to stress may help the body optimize performance to frequently encountered stressors. This may occur during chronic stress. In animal models, chronic stress exposure reorganizes neural networks regulating neuroendocrine function, providing an anatomical basis for more excitable cortisol responses to stress (Miklos and Kovacs, 2012). Hence, we propose that “anticipatory” cortisol reactivity (i.e., increases during psychological anticipation of the stressor) may be an important marker of a central nervous system that is “primed” for heightened stress-reactivity. Chronically stressed individuals may develop a heightened tendency to anticipate stress and mount a rapid cortisol response, which could increase vulnerability to oxidative stress and accelerate biological aging (Drabant et al., 2011; O'Donovan et al., 2012; Tomiyama et al., 2012)."

"The stress individuals experience as they anticipate a future event arises from their emotional and cognitive representations of what they believe or fear they will experience, rather than what they actually experience during the event. Moreover, some evidence suggests that chronic stress exposure may change the morphology of the brain regions that regulate neuroendocrine activity, promoting increased excitability of CRH neurons during stress (Miklos and Kovacs, 2012). Hence, chronic stress may predispose individuals to anticipate stress before the event occurs and mount a stronger corresponding cortisol response. These data, building upon previous findings in this sample (O'Donovan et al., 2012), underscore the important role of stress anticipation in relation to accelerated biological aging."

"Chronic stress-related alterations in biomarkers are often interpreted as a manifestation of “wear and tear” on the body or allostatic load (McEwen, 2004), as though the system were a rubber band that lost elasticity. However, an alternative and nonexclusive interpretation is that these changes may represent not so much a loss of resources, but a reallocation. Chronic stress reorganizes the structure of the central nervous system, providing an anatomical basis for changes in the dynamics (e.g., anticipatory reactivity) of stress hormones (Miklos and Kovacs, 2012). These changes may constitute an “intended” optimization of neuroendocrine system function, which has unfortunate “side effects”– i.e., the optimization increases short-term capacity for efficient responses to stress, while increasing long-term vulnerability to age-related disease. Seen from this light, heightened cortisol reactivity may not be a dysfunction or failure of the system per se, but an adaptation to cope with a demanding environment, which may have short term benefits to survival but longer term adverse consequences for healthy aging."

"Certain types of physiological stress, such as periodic exercise, are known to promote long-term decreases in circulating indicators of oxidative damage, apparently due to upregulation of antioxidant and other cytoprotective mechanisms (Radak et al., 2005). While purely speculative, it is conceivable that low-to-moderate episodic psychological stress exposure could improve psychobiological resilience to oxidative damage in a manner similar to exercise."

Thanks for this, very interesting
 

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