Why Zebras Don't Get Ulcers: The Acclaimed Guide to Stress, Stress-Related Diseases, and Coping

by Robert M. Sapolsky

time-series analysis,

Helicobacter pylori turns out to be able to live in the acidic stomach environment, protecting itself by having a structure that is particularly acid-resistant and by wrapping itself in a coat of protective bicarbonate. And this bacterium probably has a lot to do with 85 to 100 percent of ulcers in Western populations (as well as with stomach cancer).

This relationship between fetal nutritional events and lifelong risks of metabolic and cardiovascular disease was first described by the epidemiologist David Barker of Southampton Hospital in England, and now goes by the name Fetal Origins of Adult Disease (FOAD). And we’re not done with this yet. Starvation is clearly a stressor, raising the question of whether the metabolic programming occurs because of the nutritional consequences of the shortage of calories, and /or because of the stressfulness of the shortage of calories. Asked another way, do non-nutritional stressors during pregnancy also induce FOAD-like effects? The answer is, yes.

Suppose you have a fetus exposed to lots of stress, say, malnutrition, and who thus programs a thrifty metabolism. Later, as an adult, she gets pregnant. She consumes normal amounts of food. Because she has that thrifty metabolism, is so good at storing away nutrients in case that fetal famine ever comes back again, her body grabs a disproportionate share of the nutrients in her bloodstream for herself. In other words, amid consuming an average amount of food, her fetus gets a less than average share of it, producing mild malnutrition. And thus programs a milder version of a thrifty metabolism. And when that fetus eventually becomes pregnant….

First, can fetal or childhood exposure to synthetic glucocorticoids have lifelong, adverse effects? Glucocorticoids (such as hydrocortisone) are prescribed in vast amounts, because of their immunosuppressive or anti-inflammatory effects. During pregnancy, they are administered to women with certain endocrine disorders or who are at risk for delivering preterm.

The first occurs at the brain. With the onset of stress, two important classes of hormones, the endorphins and enkephalins (mostly the former), act to block the release of LHRH from the hypothalamus. As will be discussed in chapter 9, endorphins play a role in blocking pain perception and are secreted in response to exercise (helping to account for the famed “runner’s high” or “endorphin high” that hits many hardy joggers around the 30-minute mark).

It not only plays a major role in the suppression of reproduction during stress and exercise, but it also is the main reason that breast feeding is such an effective form of contraception.

The hunter-gatherer pattern, the one that has occurred throughout most of human history, is what you see in nonhuman primates. Perhaps some of the gynecological diseases that plague modern westernized women have something to do with this activation of a major piece of physiological machinery hundreds of times when it may have evolved to be used only twenty times; an example of this is probably endometriosis (having uterine lining thickening and sloughing off in places in the pelvis and abdominal wall where it doesn’t belong), which is more common among women with fewer pregnancies and who start at a later age.*

psychoneuroimmunologist—who makes a living studying the extraordinary fact that what goes on in your head can affect how well your immune system functions.

conditioned immunosuppression. Give an animal a drug that suppresses the immune system. Along with it, provide, à la Pavlov’s experiments, a “conditioned stimulus”—for example, an artificially flavored drink, something that the animal will associate with the suppressive drug. A few days later, present the conditioned stimulus by itself—and down goes immune function.

Such immune defenses are brought about by a complex array of circulating cells called lymphocytes and monocytes (which are collectively known as white blood cells; cyte is a term for cells). There are two classes of lymphocytes: T cells and B cells. Both originate in the bone marrow, but T cells migrate to mature in the thymus (hence the T), while B cells mature in the bone marrow. B cells principally produce antibodies, but there are several kinds of T cells (T helper and T suppressor cells, cytotoxic killer cells, and so on).

T cells bring about cell-mediated immunity (illustration). When an infectious agent invades the body, it is recognized by a type of monocyte called a macrophage, which presents the foreign particle to a T helper cell. A metaphorical alarm is now sounded, and T cells begin to proliferate in response to the invasion. This alarm system ultimately results in the activation and proliferation of cytotoxic killer cells, which, as their name implies, attack and destroy the infectious agent. It is this, the T-cell component of the immune system, that is knocked out by the AIDS virus.

By contrast, B cells cause antibody-mediated immunity (illustration). Once the macrophage–T helper cell collaboration has occurred, the T helper cells then stimulate B-cell proliferation. The main task of the B cells is to differentiate and generate antibodies, large proteins that will recognize and bind to some specific feature of the invading infectious agent (typically, a distinctive surface protein). This specificity is critical—the antibody formed has a fairly unique shape, which will conform perfectly to the shape of the distinctive feature of the invader, ...

The smaller the thymus, the more glucocorticoids in the circulation. Glucocorticoids halt the formation of new lymphocytes in the thymus, and most of the thymic tissue is made up of these new cells, ready to be secreted into the bloodstream. Because glucocorticoids inhibit the release of messengers like interleukins and interferons, they also make circulating lymphocytes less responsive to an infectious alarm. Glucocorticoids, moreover, cause lymphocytes to be yanked out of the circulation and stuck back in storage in immune tissues. Most of these glucocorticoid effects are against T cells, rather than B cells, meaning that cell-mediated immunity is more disrupted than antibody-mediated immunity. And most impressively, glucocorticoids can actually kill lymphocytes. This taps into one of the hottest topics in medicine, which is the field of “programmed cell death.”* Cells are programmed to commit suicide sometimes. For example, if a cell begins to become cancerous, there is a suicide pathway that gets activated to kill the cell before it starts dividing out of control; a few types of cancers involve the failure of the programmed cell death to occur. It turns out that glucocorticoids can trigger those suicide pathways into action in lymphocytes, through a variety of mechanisms.

During infections, the immune system releases the chemical messenger interleukin-1, which among other activities stimulates the hypothalamus to release CRH. As noted in chapter 2, CRH stimulates the pituitary to release ACTH, which then causes adrenal release of glucocorticoids. These in turn suppress the immune system. In other words, under some circumstances, the immune system will ask the body to secrete hormones that will ultimately suppress the immune system. For whatever reason the immunosuppression occurs, the immune system sometimes encourages it. It is probably not just an accident.

This boosting of immunity doesn’t occur only after some infectious challenge. Physical stressors, psychological stressors, all appear to cause an early stage of immune activation. Even more surprisingly, those immunosuppressive villains, glucocorticoids, appear to play a major role in this (along with the sympathetic nervous system).

And that’s what can happen with immune systems that are chronically activated—they begin to mistake part of you for being something invasive, and you’ve got yourself an autoimmune disease. Such reasoning led Munck to predict that if you fail to have phase B, if you don’t coast that activated immune system back down to baseline, you’re more at risk for an autoimmune disease.

they all turn out to have something wrong with the glucocorticoid system so that they have lower than normal levels of the hormone, or have immune and inflammatory cells that are less responsive than normal to glucocorticoids. Same for humans with autoimmune diseases like rheumatoid arthritis.

Why do people with RA get sick, with such high level of immunity?

Supporting this summary is the finding that while acute stress puts rats more at risk for a model of multiple sclerosis, chronic stress suppresses the symptoms of that autoimmune disease.

How does a latent herpes virus that, after all, is just some unschooled little stretch of DNA sitting mothballed inside a bunch of your neurons, know that you are immunosuppressed? One possibility is that herpes is always attempting to come out of latency and, if your immune system is working fine, it snuffs out the attempt. A second possibility is that herpes can somehow measure how the immune system is doing. Amazingly, the answer has emerged in the last few years. Herpes doesn’t measure how your immune system is doing. It measures something else that, for its purposes, gives it the information it needs—it measures your glucocorticoid levels. Herpes DNA contains a stretch that is sensitive to elevated glucocorticoid signals, and when levels are up, that DNA sensor activates the genes involved in coming out of latency. Epstein-Barr and varicella-zoster contain this glucocorticoid-sensitive stretch as well.

And now for something even more fiendishly clever. You know what else herpes can do once it infects your nervous system? It causes your hypothalamus to release CRH which releases ACTH which raises glucocorticoid levels.

The strength of a pain signal, for example, can depend on what other sensory information is funneled to the spine at the same time. This, it turns out, is why it feels great to have a massage when you have sore muscles. Chronic, throbbing pain can be inhibited by certain types of sharp, brief sensory stimulation.

The pain physiologist David Yeomans has framed the functions of the fast and slow fibers in a way that fits perfectly with this book: what the fast fibers are about is getting you to move as quickly as possible (from the source of the piercing pain). What the slow fibers are about is getting you to hunker down, immobile, so you can heal.

This adds to the pain for an instant, but by stimulating the Y interneuron, you shut the system down for a while. And that is precisely what we often do in all of those circumstances. Experiencing a good vigorous mauling massage inhibits the dull throbbing pain of sore muscles for a while. An insect bite throbs and itches unbearably, and we often scratch hard right around it to dull the pain.

The Wall-Melzack pathway model explains another instance of allodynia, as seen in severe cases of both types of diabetes. As we saw in chapter 4, elevated levels of glucose in the bloodstream can increase the risk of atherosclerotic plaques, clogging up blood vessels. As a result, insufficient energy gets through those vessels, potentially damaging nerves that depend on that energy. In general it is the fast fibers, which take more energy to operate than the lower-maintenance slow fibers, that are damaged. Thus, the person loses the ability to shut down the Y interneuron in that pathway, and what would be a transient pain for anyone else becomes a constant throbbing one for a diabetic.

But most of what the brain’s responses to pain are about is generating emotional responses and giving contextual interpretations about the pain.

First, the emotional/interpretative level can be dissociated from the objective amount of pain signal that is coursing up to the brain from the spine. In other words, how much pain you feel, and how unpleasant that pain feels, can be two separate things.

As a second point, those more emotive parts of the brain not only can alter how you respond to pain information coming up the spinal cord; those areas of the brain can alter how the spinal cord responds to pain information. And the third point: this is where stress comes in big time.

During REM sleep, metabolism in the frontal cortex goes way down, disinhibiting the limbic system to come up with the most outlandish ideas. That’s why dreams are dreamlike—illogical, nonsequential, hyperemotional.

So, lots of stress and, potentially, little sleep. But stress not only can decrease the total amount of sleep but can compromise the quality of whatever sleep you do manage. For example, when CRH infusion decreases the total amount of sleep, it’s predominantly due to a decrease in slow wave sleep, exactly the type of sleep you need for energy restoration. Instead, your sleep is dominated by more shallow sleep stages, meaning you wake up more easily—fragmented sleep.

This teaches us a lot about what counts as good sleep and how stress can prevent it. But as we’ll see in a couple of chapters, this generalizes beyond sleep. When it comes to what makes for psychological stress, a lack of predictability and control are at the top of the list of things you want to avoid.

With that rite of passage, he has found the mother lode of psychic energy that fuels our most irrational and violent moments, our most selfish and our most altruistic ones, our neurotic dialectic of simultaneously mourning and denying, our diets and exercising, our myths of paradise and resurrection. It’s as if we were trapped in a mine, shouting out for rescuers, Save us, we’re alive but we’re getting old and we’re going to die.

So sometimes the problem in aging is not enough of a stress-response. Predictably, in some realms, the problem is too much of a stress-response—either one turned on all the time, or one that takes too long to turn off at the end of a stressor.

At least twice in evolutionary history, completely independently, two very different sets of species have come up with the identical trick: if you want to degenerate very fast, secrete a ton of glucocorticoids.

the physiological stress-response can be modulated by psychological factors. Two identical stressors with the same extent of allostatic disruption can be perceived, can be appraised differently, and the whole show changes from there.

The Building Blocks of Psychological Stressors Outlets for frustration

A central feature of an outlet being effective is if it distracts from the stressor. But, obviously, more important is that it also be something positive for you—a reminder that there is more to life than whatever is making you crazed and stressed at the time. The frustration-reducing effects of exercise provide an additional layer of benefit, one harking back to my dichotomy, repeated ad nauseam, between the zebra running for its life and the psychologically stressed human.

A variant of Weiss’s experiment uncovers a special feature of the outlet-for-frustration reaction. This time, when the rat gets the identical series of electric shocks and is upset, it can run across the cage, sit next to another rat and…bite the hell out of it. Stress-induced displacement of aggression: the practice works wonders at minimizing the stressfulness of a stressor. It’s a real primate specialty as well. A male baboon loses a fight. Frustrated, he spins around and attacks a subordinate male who was minding his own business. An extremely high percentage of primate aggression represents frustration displaced onto innocent bystanders.

Social support

Predictability Weiss’s rat studies uncovered another variable modulating the stress-response. The rat gets the same pattern of electric shocks, but this time, just before each shock, it hears a warning bell. Fewer ulcers. Predictability makes stressors less stressful.

In the absence of any stressor, loss of predictability triggers a stress-response.

Among other reasons, we wish to optimize our coping strategies when we request the most devastating piece of medical information any of us will ever face: “How much time do I have left?”

Control

Thus, the exercise of control is not critical; rather, it is the belief that you have it. An everyday example: airplanes are safer than cars, yet more of us are phobic about flying. Why? Because your average driver believes that he is a better-than-average driver, thus more in control.

Endless studies have shown that the link between occupational stress and increased risk of cardiovascular and metabolic diseases is anchored in the killer combination of high demand and low control—you have to work hard, a lot is expected of you, and you have minimal control over the process. This is the epitome of the assembly line, the combination of stressors that makes for Marx’s alienation of the workers.

So the variable of control is extremely important; controlling the rewards that you get can be more desirable than getting them for nothing. As an extraordinary example, both pigeons and rats prefer to press a lever in order to obtain food (so long as the task is not too difficult) over having the food delivered freely—a

A perception of things worsening

It’s not just the external reality; it’s the meaning you attach to it.

Sometimes these different variables conflict and it becomes a question as to which is more powerful. This often involves a dichotomy between control/predictability issues and the perception of whether things are improving or worsening.

These factors play a major role in explaining how we all go through lives full of stressors, yet differ so dramatically in our vulnerability to them.