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

by Robert M. Sapolsky

A large body of evidence suggests that stress-related disease emerges, predominantly, out of the fact that we so often activate a physiological system that has evolved for responding to acute physical emergencies, but we turn it on for months on end, worrying about mortgages, relationships, and promotions.

The brain, it has been noted, has evolved to seek homeostasis.

This allows us to generate some simple initial working definitions that would suffice for a zebra or a lion. A stressor is anything in the outside world that knocks you out of homeostatic balance, and the stress-response is what your body does to reestablish homeostasis.

The original conception of homeostasis was grounded in two ideas. First, there is a single optimal level, number, amount for any given measure in the body. But that can’t be true—after all, the ideal blood pressure when you’re sleeping is likely to be different than when you’re ski jumping. What’s ideal under basal conditions is different than during stress, something central to allostatic thinking. (The field uses this Zen-ish sound bite about how allostasis is about “constancy through change.” I’m not completely sure I understand what that means, but it always elicits meaningful and reinforcing nods when I toss it out in a lecture.) The second idea in homeostasis is that you reach that ideal set point through some local regulatory mechanism, whereas allostasis recognizes that any given set point can be regulated in a zillion different ways, each with its own consequences.

thirsty. Homeostasis is about tinkering with this valve or that gizmo. Allostasis is about the brain coordinating body-wide changes, often including changes in behavior.

Within this expanded framework, a stressor can be defined as anything that throws your body out of allostatic balance and the stress-response is your body’s attempt to restore allostasis.

And regardless of the stressor—injured, starving, too hot, too cold, or psychologically stressed—you turn on the same stress-response.

One of the hallmarks of the stress-response is the rapid mobilization of energy from storage sites and the inhibition of further storage. Glucose and the simplest forms of proteins and fats come pouring out of your fat cells, liver, and muscles, all to stoke whichever muscles are struggling to save your neck.

Finally, during stress, shifts occur in cognitive and sensory skills. Suddenly certain aspects of memory improve, which is always helpful if you’re trying to figure out how to get out of an emergency (Has this happened before? Is there a good hiding place?). Moreover, your senses become sharper. Think about watching a terrifying movie on television, on the edge of your seat at the tensest part. The slightest noise—a creaking door—and you nearly jump out of your skin. Better memory, sharper detection of sensations—all quite adaptive and helpful.

It is not so much that the stress-response runs out, but rather, with sufficient activation, that the stress-response can become more damaging than the stressor itself, especially when the stress is purely psychological. This is a critical concept, because it underlies the emergence of much stress-related disease.

if you plan to get stressed like a normal mammal, dealing with an acute physical challenge, and you cannot appropriately turn on the stress-response, you’re in big trouble. To see this, all you have to do is examine someone who cannot activate the stress-response.

On a superficial level, the message it imparts might seem to be that stressors make you sick or, as emphasized in the last few pages, that chronic or repeated stressors make you sick. It is actually more accurate to say that chronic or repeated stressors can potentially make you sick or can increase your risk of being sick. Stressors, even if massive, repetitive, or chronic in nature, do not automatically lead to illness. And the theme of the last section of this book is to make sense of why some people develop stress-related diseases more readily than others, despite the same stressor.

sick. Stress increases your risk of getting diseases that make you sick, or if you have such a disease, stress increases the risk of your defenses being overwhelmed by the disease.

Thus, medical practitioners often say, in effect, “You feel sick because you have disease X, not because of some nonsense having to do with stress; however, this ignores the stressors’ role in bringing about or worsening the disease in the first place.

Epinephrine is secreted as a result of the actions of the sympathetic nerve endings in your adrenal glands (located just above your kidneys); norepinephrine is secreted by all the other sympathetic nerve endings throughout the body. These are the chemical messengers that kick various organs into gear, within seconds.

when the sympathetic nerve endings in your heart secrete norepinephrine, which causes heart muscle to work differently, norepinephrine is playing a neurotransmitter role. If a neuron (or any cell) secretes a messenger that, instead, percolates into the bloodstream and affects events far and wide, that messenger is a hormone. All sorts of glands secrete hormones; the secretion of some of them is turned on during stress, and the secretion of others is turned off.

Put in a brand-new set of testes and they should fail also, for lack of a stimulatory signal.

that if you removed the pituitary from a body and put it in a small bowl filled with pituitary nutrients, the gland would act abnormally. Various hormones that it would normally secrete were no longer secreted. Sure, you might say, remove any organ and throw it in some nutrient soup and it isn’t going to be good for much of anything. But, interestingly, while this “explanted” pituitary stopped secreting certain hormones, it secreted others at immensely high rates. It wasn’t just that the pituitary was traumatized and had shut down. It was acting erratically because, it turned out, the pituitary didn’t really have the whole hormonal game plan. It would normally be following orders from the brain, and there was no brain on hand in that small bowl to give directions.

So hooray for Guillemin and Schally; the brain turned out to be the master gland. It is now recognized that the base of the brain, the hypothalamus, contains a huge array of those releasing and inhibiting hormones, which instruct the pituitary, which in turn regulates the secretions of the peripheral glands.

Two hormones vital to the stress-response, as already noted, are epinephrine and norepinephrine, released by the sympathetic nervous system. Another important class of hormones in the response to stress are called glucocorticoids. By the end of this book you will be astonishingly informed about glucocorticoid trivia, since I am in love with these hormones. Glucocorticoids are steroid hormones. (Steroid is used to describe the general chemical structure of five classes of hormones: androgens—the famed “anabolic” steroids like testosterone that get you thrown out of the Olympics—estrogens, progestins, mineralocorticoids, and glucocorticoids.) Secreted by the adrenal gland, they often act, as we will see, in ways similar to epinephrine. Epinephrine acts within seconds; glucocorticoids back this activity up over the course of minutes or hours.

Taylor suggests that rather than the female stress-response being about fight-or-flight, it’s about “tend and befriend”—taking care of her young and seeking social affiliation. As will be seen in the final chapter of the book, there are some striking gender differences in stress management styles that support Taylor’s view, many of them built around the propensity toward social affiliation.

Nevertheless, amid these criticisms, there is a widespread acceptance of the idea that the body does not respond to stress merely by preparing for aggression or escape, and that there are important gender differences in the physiology and psychology of stress.

Sympathetic arousal is a relative marker of anxiety and vigilance, while heavy secretion of glucocorticoids is more a marker of depression.

Thus, chronic stress can cause hypertension and atherosclerosis—the accumulation of these plaques.

So stress can increase the risk of atherosclerosis. Form enough atherosclerotic plaques to seriously obstruct flow to the lower half of the body and you get claudication, which means that your legs and chest hurt like hell for lack of oxygen and glucose whenever you walk; you are then a candidate for bypass surgery. If the same thing happens to the arteries going to your heart, you can get coronary heart disease, myocardial ischemia, all sorts of horrible things.

Whenever you inhale, you turn on the sympathetic nervous system slightly, minutely speeding up your heart. And when you exhale, the parasympathetic half turns on, activating your vagus nerve in order to slow things down (this is why many forms of meditation are built around extended exhalations).

He identified a number of events that seemed to be associated with such deaths: the collapse, death, or threat of loss of someone close; acute grief; loss of status or self-esteem; mourning, on an anniversary; personal danger; threat of an injury, or recovery from such a threat; triumph or extreme joy.

When it comes to the cardiovascular system, rage and ecstasy, grief and triumph all represent challenges to allostatic equilibrium.

estrogen plus progestin was so clearly increasing the risk of heart disease and stroke (while still protecting against osteoporosis) that it was unethical to continue the study.

the laboratory studies suggest that estrogen protects against the formation of atherosclerosis, rather than reverses atherosclerosis that is already there. This is quite relevant because, given our Western diets, people are probably just starting to form atherosclerotic plaques in their thirties, not in their post-menopausal fifties or sixties.

Amino acids are not a very good source of energy, but glucose is. Your body shunts the circulating amino acids to the liver, where they are converted to glucose.

Finally, another problem with constantly mobilizing the metabolic stress-response was hinted at in the last chapter. You don’t want to have tons of fat and glucose perpetually circulating in your bloodstream because, as we saw, that increases the chances of the stuff glomming on to some damaged blood vessel and worsening atherosclerosis.

Stress promotes insulin resistance.

Thus, frequent stress and/or big stress-responses might increase the odds of getting juvenile diabetes, accelerate the development of the diabetes, and, once it is established, cause major complications in this life-shortening disease.* Therefore, this is a population in which successful stress management is critical.

Technically, nothing is wrong, amid it being obvious that things are not right. Take more than a thousand study subjects, all over age seventy, none of whom are certifiably sick—that is to say, where none of those measures are technically abnormal. Now, see how they’re doing on all those Metabolic syndrome measures. Throw in some other measures as well—including resting levels of glucocorticoids, epinephrine, norepinephrine. Combine the insights into these measures mathematically and, collectively, this information was significantly predictive of who was going to have heart disease, a decline in cognitive or physical functioning, and mortality, far more predictive than subsets of those variables alone.

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CRH inhibits appetite, glucocorticoids do the opposite.* Yet they are both hormones secreted during stress.

Therefore, if there are large amounts of CRH in your bloodstream, yet almost no glucocorticoids, it is a safe bet that you are in the first few minutes of a stressful event. Good time to turn off appetite, and the combination of high CRH and low glucocorticoids accomplishes that.

when given an array of foods to choose from during the post-stress period, they also atypically crave sweets. This is an effect that is specific to stress.

turns out that when glucocorticoids stimulate fat deposition, they do it preferentially in the abdomen, promoting apple-shaped obesity. This even occurs in monkeys. The pattern arises because abdominal fat cells are more sensitive to glucocorticoids than are gluteal fat cells; the former have more receptors that respond to glucocorticoids by activating those fat-storing enzymes. Furthermore, glucocorticoids only do this in the presence of high insulin levels.

prolonged glucocorticoid response to novelty is a feature of applish people, not pears.

There seems to be a huge number of routes by which obesity can occur—too much or too little of this or that hormone; too much or too little sensitivity to this or that hormone.* But another route appears to involve being the sort of person who secretes too many glucocorticoids, either because of too many stressors, too many perceived stressors, or trouble turning off the stress-response.

One reason for this is the linkage between IBS and certain personality types. In the cases of depression or anxiety, the connection is solid, but earlier linkages seem pretty suspect. These studies tended to focus on a lot of psychoanalytic gibberish (there, now I’ll get myself into trouble with that crowd)—some hoo-ha about the person being stuck in the anal stage of development, a regression to the period of toilet training where going to the bathroom gained great acclaim and, suddenly, diarrhea was a symbolic reach for parental approval. Or the approval of the doctor as a parental surrogate. Or something or other. I’m not sure how they factored in constipation, but I’m sure they did.

Along comes a stressful period that lasts months. Your body cuts down on its acid secretion—there are now frequent times when digestion is being inhibited. During this period, your stomach essentially decides to save itself some energy by cutting corners. It cuts back a bit on the constant thickening of the stomach walls, undersecretes mucus and bicarbonate, and pockets the difference. Why not? There isn’t much acid around during this stressful period anyway.

the kids did not spontaneously burst out of the door one day reciting poetry in Italian or singing opera. The kids didn’t burst out of the door at all. None of them survived. The lesson is obvious to us now—optimal growth and development do not merely depend on being fed the right number of calories and being

Studying premature infants in neonatology wards, they noted that the premature kids, while pampered and fretted over and maintained in near-sterile conditions, were hardly ever touched. So Field and crew went in and started touching them: fifteen-minute periods, three times a day, stroking their bodies, moving their limbs. It worked wonders. The kids grew nearly 50 percent faster, were more active and alert, matured faster behaviorally, and were released from the hospital nearly a week earlier than the premature infants who weren’t touched. Months later, they were still doing better than infants who hadn’t been touched.

There is little evidence that any of these childhood experiences leave indelible biological scars, in contrast to the results of horrific childhood trauma. But whatever style of child-rearing is practiced, it will have its consequences. Small makes a profound point. You begin by reading her book assuming it is going to be an assortment box of prescriptions, that at the end, you’ll emerge with a perfect combo for your kids, a mixture of the Kwakiutl Baby Diet, the Trobriand Sleeping Program, and the Ituri Pygmy Infant Aerobics Plan. But, Small emphasizes, there is no perfect, “natural” program. Societies raise their children so that they grow into adults who behave in a way valued by that society. As Harry Chapin sang in “Cat’s in the Cradle,” that ode to baby boomer remorse, “My boy was just like me.”

Estrogen potently inhibits bone resorption, and as estrogen levels drop after menopause, the bones suddenly begin to degenerate.* A hefty regimen of glucocorticoids on top of that is the last thing you need.

A decline in testosterone secretion is only half the story of what goes wrong with male reproduction during stress. The other half concerns the nervous system and erections. Getting an erection to work properly is so incredibly complicated physiologically that if men ever actually had to understand it, none of us would be here. Fortunately, it runs automatically. In order for a male primate to have an erection, he has to divert a considerable amount of blood flow to his penis, engorging it.* This is accomplished by activating his parasympathetic nervous system. In other words, the guy has to be calm, vegetative, relaxed.

No wonder when it’s dawn on the savanna the hyenas on the periphery are looking cranky, with circles under their eyes. They stayed up all night hunting that thing, and who’s having breakfast now?

Among many social mammals, males have erections during competitive situations as a sign of dominance. If you are having a dominance display with another male, you get an erection and wave it around in his face to show what a tough guy you are. Social primates do this all the time.