In his book, The End of Stress As We Know It, noted researcher Bruce McEwen says that the "fight-or-flight" response that helps us survive threatening situations can eventually turn against us. Damage occurs if we are exposed to repeated or chronic stress, and the body remains in a state of high alert for long periods of time.
Stress hormones accelerate heart rate and blood pressure to give us the burst of energy needed to confront or run way from danger. But when these same hormones are sustained at high levels or become deregulated, we are predisposed to a wide range of illnesses, including heart disease, high blood pressure, hardening of the arteries, diabetes, and depression.
Stress-related ailments now cost the American economy over $220 billion annually. To combat this trend, Dr. McEwen and his colleagues are exploring the physiology of stress and ways to deal with the threat of chronic overload.
Of special interest, says Dr. McEwen, is ongoing research on the stress hormone cortisol. Some examples: Stanford University researcher David Speigel MD recently found that breast cancer patients with higher evening cortisol levels have a shorter life expectancy. Other investigators note that higher cortisol levels are associated with diabetes, hypertension, and a less-than-optimal immune system. Further, an exaggerated response to the stress hormone cortisol might predict whether someone will develop alcoholism later in life.
At The Rockefeller University in New York, Dr. McEwen is currently studying the effects of stress hormones on the brain. In addition, he is also identifying differences between the male and female stress response.
Our managing editor, Valerie Andrews, recently spoke with Dr. McEwen about the overall dangers of chronic stress and how we might reduce the load with lifestyle changes and new medications.
His book, The End of Stress, has just been released in paperback by The National Academies Press.
What biological processes speed up to help us deal with a threatening situation?
The classic "fight-or-flight" response means increased production of the stress hormones adrenaline and noradrenaline and cortisol. These bring about changes in the brain, metabolism, and heart rate.
Cortisol and adrenaline enhance memory processes, helping us to store and retrieve sensory cues and be alert to future danger.
Metabolism accelerates and energy supplies are mobilized to handle the emergency and replenish fuel.
We also see increased immune function. Immune cells can move more quickly from the bloodstream to the tissues to help us deal with a wound or infection.
The body does all this in response to acute stress.
What happens when we suffer from chronic or repeated stress?
The systems that were enhanced by the "fight-or-flight" response are eventually impaired.
The body produces the same hormones as it does to deal with acute stress, but they are no longer properly regulated.
These hormones may repeatedly spike, or they may fail to shut off when no longer needed.
When stress hormones remain high for many more hours after the triggering event, they have a backlash effect: Instead of activating the immune system, they suppress it.
Instead of helping us to think more clearly, they cause the nerve cells in the brain to shrink. Excitatory amino acid transmitters are also over-produced. They remain active even after the nerve cell fires - and, as a result, we see damage to the hippocampus. As a result, memory is impaired. Instead of giving us a more efficient metabolism, they convert energy sources into fat.
Chronic stress is associated with abdominal fat deposits. Inflammatory cytokines also increase, and this can lead to hardening of the arteries.
The take-home message is this: The same agents that promote adaptation can also create a condition of allostatic overload.
What do you mean by term "allostatic overload," and why is this concept so important?
We use the word "stress" when we think about the "fight-or- flight" response. We picture an animal focused on survival being chased by a predator in the wild. It's a one-time response.
Then the body calms down. The term homeostasis refers to an organism's ability to maintain this steady state. It comes from the Greek roots homeo, meaning "same," and stasis, meaning "stable."
But we need a new and more wide-ranging definition of stress to describe what happens to the body in the modern age. Today, many things build up over time and throw the stress response off kilter: sleep loss, overwork, lack of social support, inadequate exercise, depression. When this happens, we go into allostatic overload.
Allostasis comes from the Greek root allo, meaning "variable," and it emphasizes the fact that the same body systems that adjust to help us deal with threatening situations - heart rate, breathing, the amount of glucose in the blood - are now having trouble shutting down and returning the body to a stable state.
Almost everything that's going on in our lives can contribute to allostatic overload.
It all funnels down to affect these same hormonal systems. And we need to learn much more about their interlocking patterns.
What have we learned so far?
The Adverse Childhood Experiences study of Kaiser Permanente in San Diego surveyed 9,000 patients and correlated childhood stress with the later development of substance abuse, depression, suicide, sexual promiscuity, heart disease, cancer, chronic lung disease, obesity, skeletal fractures, and liver disease.
Childhood stress is already linked to the development of asthma and insulin-dependent diabetes.
Studies in the workplace show that people on the lowest rung of the decision-making ladder suffer the most stress because they feel they have the least control over their environment.
Sheldon Cohen at Carnegie Mellon University found that the ongoing stress of unemployment and social isolation can make individuals more susceptible to the common cold. Marital strain can also undermine our immune defenses, according to Ron Glaser and Janice Kiecolt-Glaser, both of Ohio State University. So can the loss of a family member. The ultimate social stressor is bereavement.
Are we more susceptible to allostatic overload as we age?
The illnesses we consider stress-related - like hardening of the arteries, diabetes, depression, arthritis - do tend to develop or get worse as people age. We also have data on increased risk of cardiovascular disease and heart attacks after menopause. Depression is certainly related to aging. It may develop earlier in life, but if it's not successfully treated, over time the hippocampus may shrink, and there may be changes in the brain.
How fast can the brain recover if the stressor is removed?
In rats, if you stop the stress at 10 weeks, you will see recovery in 7 to 10 days.
We have some indicator of recovery time for humans if we look at Cushing's disease. This condition arises from a pituitary tumor that drives the adrenal cortex and produces elevated cortisol. If you correct this condition with surgery, it takes a year or longer to see significant reversal of shrinkage in the hippocampus. This gives us hope that the damage to this area of the brain isn't permanent.
We don't know the full story about the effects of long-term depression yet. Antidepressants and mood-stabilizing drugs like lithium may help or reserve the shrinkage of the hippocampus. And psychiatrists in St. Louis and at Emory University in Atlanta are now using brain imaging to determine how fast this portion of the brain can recover.
What is the link between sleep disturbances and cortisol uptake and disease?
One of the most powerful sources of allostatic load is sleep deprivation. Cortisol levels are elevated in the evening when they should be down. Blood pressure tends to go up then, as well, a time when it, too, should be down.
Parasympathetic activity is reduced, so the heart is operating more on sympathetic activation. There's increased production of inflammatory cytokines as a result. And we also see increased appetite. People who are sleep-deprived crave the wrong things and eat at the wrong time of day. As a result, the food goes to their mid-section because the liver handles fuel in a different way at different times of the day and converts more of it into fat.
So sleep deprivation alone can have many negative consequences. Sleep deprivation is also a feature of depression and may be related to changes in body type. Depressed women not only have increased abdominal fat, they lose minerals from their bones due to changes in their cortisol levels. They also have increased risk of cardiovascular disease.
What is the relationship of stress to diabetes and insulin resistance?
This is one more result of allostatic overload. Diabetes occurs more often in people with certain genetic traits, but the body can be pushed in that direction by sleep deprivation and depression.
A new report from the Rush University Medical Center in Chicago shows that Type II diabetes is a risk factor for Alzheimer's disease. So we have a web effect that reaches into several different systems.
Do inflammatory diseases increase when stress goads the immune system into overdrive?
Yes. Any kind of autoimmune disorder like multiple sclerosis or rheumatoid arthritis is exacerbated by stress. So are inflammatory processes like allergies and asthma. Stress produces elevated catecholamines that, in turn, increase the production of inflammatory cytokines. The same healing process that helps us fight a wound or a pathogen can work against us if we have too much stress and start to produce an immune reaction against our own bodies.
What do we know about the relationship of stress and sexual response?
Sexual activity can be affected by both psychological and physical stress. Christina Heim, of the University of Trier, studied women with post-traumatic stress disorder (PTSD), depression, and pelvic pain and measured their cortisol levels. She found a link a between chronic pelvic pain, a higher incidence of sexual/physical abuse, and blunted cortisol response.
Do men and women respond to stress differently?
That's a good question. Women and men produce the same stress hormones in roughly the same amounts but not always under the same circumstances.
Men, for example, tend to be more stressed out by things that have to do with mastery and things that may threaten their ego. In a driving simulation challenge, for example, they feel more under the gun than women because they want to achieve the best possible score.
Men appear to be less stressed when they are addressing a crowd if they are also accompanied by a supportive spouse. Women tend to be more stressed in these situations if they have their husbands with them; they do better with female support.
These are behavioral studies, and they don't tell us what's going on with the physiology. Investigators are now trying to understand that link.
So far, we've found that gonadal hormones-testosterone in males and estrogen in females-seem to have a calming influence.
Conversely, males with low androgen levels are more susceptible to stress. And post-menopausal women who are not taking estrogen replacement show greater increases in adrenaline and cortisol.
These hormones are also linked to changes in the brain. Estrogen seems to alter the way the hippocampus responds to chronic stress. Studies of female rats show less shrinkage of nerve cells in the hippocampus as long as the rat has working ovaries - that is, as long as she is producing estrogen. Tracey Shors at Rutgers University in Newark, N.J., has also found that male and female rats respond differently to stress in learning situations.
Here's an example: Researchers provide an audio tone at the same time as they send a puff of air into the animal's eye. The rat learns to blink when it hears the tone. This is classical Pavlovian conditioning. If a male mouse receives a shock at the same time, the learning process is enhanced. But the same kind of shock hampers the performance of the female.
Now here's the interesting thing: Investigators found that if you give the female testosterone at birth and change the phenotypic sex, she will have more male characteristics, and in this learning situation her response will be more like the male's. The shock will tend to enhance her learning process.
By the same token, if you block androgen secretion in utero for the male, he will behave more like the females, and the shock will interfere with his performance. In short, profound behavioral differences are related to presence or absence of testosterone.
How does stress affect the different sections of the brain?
We are looking at what happens to the amygdala - or what's been called the "seat of emotion" - in response to repeated stress.
I've noted that in the hippocampus the nerve cells shrink in response to repeated stress. But in the amygdala the nerve cells being to grow and produce more dendrites. This is linked to increased anxiety and fear.
Subject a rat to a single traumatic stressor, say, restraining its movement, and within a matter of hours, there is a growth response in the amygdala. Over a course of days, without providing any additional stress, you will see a formation of new synaptic connections.
This may be related to post-traumatic stress disorder in humans. This mechanism might explain why some people have a sustained fear response after a harrowing event. We've also found that the prefrontal cortex also shrinks in response to repeated stress.
When all these things add up - shrinkage of the pre-frontal cortex and hippocampus, along with a growth response in the amygdala - you get an animal that is less able to handle memory tasks, has poor spatial orientation, and has a poor working memory. It also has a hard time shutting off fearrelated behavior.
The pre-frontal cortex is involved in what we call the "extinction of learning." In human decision making this is what enables us to turn off the ongoing activity and start something new.
There are three phases to this process: initial learning, consolidation of the learning, and then unlearning. Unlearning is an erasure of the original memory by means of new learning superimposed on top of it. Unlearning is also a reframing of the original event-one that tells you that the initial cues are not as important. If a stressful situation recurs, the old learning will serve you, and you will react instinctively. What's hot in the area of brain research is this reconsolidation, or unlearning, process. The basic principles were discovered a long time ago and then forgotten. Consider the following example: Move a rat or mouse from a small chamber into a larger one, where it receives a foot shock. Next time, it will hesitate to enter the bigger chamber. If, the next day, you put the animal back in the larger chamber and don't give it a shock, you will start to foster the extinction of learning. The animal will gradually extinguish its fear and walk into this space readily.
During the original experiment, however, you can block the learning process by injecting a substance that inhibits protein synthesis in the brain. The animal won't remember receiving the shock, but the next time it is put back into the larger chamber, it will hesitate. Why? Because the brain has recovered a memory trace.
Researchers can suppress even that memory trace by repeating the experiment again. The ability to reactivate memories and then "inactivate" them is called reconsolidation. What this tells us is that memories can be suppressed and possibly even removed.
How does this insight apply to humans?
Investigators at the University of California and Harvard have found that beta-adrenergic receptors are powerfully linked to fear-related memories and flashbacks. If we put people into a situation that recalls a past trauma and give them a beta-blocker, the medication appears to blunt the trauma's effect. The person is less fearful because the drug is blocking the reconsolidation of these memories. In this way, we may eventually help people to suppress traumatic memories biologically. This is a promising area of research.
In your book, you refer to a new way to treat accident victims who are likely to develop post-traumatic stress disorder (PTSD).
Yes. German researchers treated septic shock patients with hydrocortisone and found that they have fewer cases of PTSD. People with PTSD tend to have low cortisol and high activity of adrenaline. It stands to reason you could treat PTSD in two ways: with beta-blockers and doses of cortisol.
What kind of behavioral or lifestyle changes help us avoid allostatic overload?
If I had to put my money on three things, I'd say regular, moderate exercise, balanced diet, and good social support. Cognitive behavioral therapy can also help. But no single approach will do the trick. You have to take all these lifestyle elements into account.
I'm involved with the MacArthur Foundation Research Network on Socioeconomic Status and Health. We're looking at why there are such regular differences in health and mortality as you go down the socioeconomic ladder, with higher rates of obesity, heart disease, diabetes, depression, and mortality at low end of scale. People who are in the middle financially are in the middle healthwise, too. People who are at the top, financially, are the healthiest. We are attempting to create a conceptual model that will tells us why this happens, and we're looking at a number of variables that also relate to allostatic overload: the kind of food consumed, the habit of eating junk food to feel better, sleep deprivation, the role of optimism and pessimism, the sense of control people have over their jobs and their lives, whether they feel secure and safe in their own neighborhoods. A central question: When people are under stress, are they more likely to compensate with smoking, drugs, and alcohol? (For more information about the MacArthur study, see www.macses.ucsf.edu). These are important issues.
Do close, loving relationships help to protect us from stress?
The hormone oxytocin (that, among other things, is responsible for initiating childbirth) seems to reduce the stress response. Researchers studying the mouse-like vole called it the "love hormone" because it's important to pair bonding. In the animal world, it's also associated with social support and reduced physiological stress.
A single-chain protein hormone called prolactin, which stimulates milk production in nursing mothers, also works to reduce anxiety. But neither oxytocin or prolactin readily cross the blood-brain barrier, so we can't just create a pill that will produce the same effect.
Some researchers have tried giving hormones like oxytocin and prolactin to patients through a nasal mist and are trying to find out if this method of delivery provides a more direct route into the brain, but we're still a long way off from devising any practical treatments.
You say that to understand the biology of stress, we need to identify the people who have the most resilience. What do you mean by that?
A 1997 study by Ryff and Singer looked at money, relationships, and life path in relation to stress or allostatic load. Not surprisingly, people with both financial stress and negative relationships, who felt they were on a downward life path, had the highest allostatic load. But the people who had the lowest allostatic load were those who gave a negative report on economic status but felt positive about their relationships and in general believed they were on an upward path.
What is this telling us about our attitude and our ability to handle stress?
Resilience is related to optimism and a sense of control and mastery and to a sense of purpose. We all know intuitively that these things make a huge difference, but we don't know have foggiest notion of how they get under the skin and are translated biologically. Our challenge is to find out how these qualities link up to the physiological mechanisms we are studying.
Researchers in neurobiology are identifying how nerve cells grow and survive and maintain healthy connections with other cells. This process may turn out to be enhanced by such things as regular exercise and positive relationships. For a long time, we've focused on the absence of health. Now we need to focus on what enables people to resist stress and to function well, and then we need to identify the biological markers that go along with it.
This article is for educational purposes only and is not intended as a substitute for medical advice. Please consult with a clinician to review any current symptoms and address your medical concerns.
