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

by Robert M. Sapolsky

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.

What Selye did was to formalize the concept with two ideas: The body has a surprisingly similar set of responses (which he called the general adaptation syndrome, but which we now call the stress-response) to a broad array of stressors. If stressors go on for too long, they can make you sick.

(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.)

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 constantly mobilize energy at the cost of energy storage, you will never store any surplus energy. You will fatigue more rapidly, and your risk of developing a form of diabetes will even increase. The consequences of chronically activating your cardiovascular system are similarly damaging: if your blood pressure rises to 180/100 when you are sprinting away from a lion, you are being adaptive, but if it is 180/100 every time you see the mess in your teenager’s bedroom, you could be heading for a cardiovascular disaster. If you constantly turn off long-term building projects, nothing is ever repaired. For paradoxical reasons that will be explained in later chapters, you become more at risk for peptic ulcers. In kids, growth can be inhibited to the point of a rare but recognized pediatric endocrine disorder—stress dwarfism—and in adults, repair and remodeling of bone and other tissues can be disrupted. If you are constantly under stress, a variety of reproductive disorders may ensue. In females, menstrual cycles can become irregular or cease entirely; in males, sperm count and testosterone levels may decline. In both sexes, interest in sexual behavior decreases.

You sit in your chair not moving a muscle, and simply think a thought, a thought having to do with feeling angry or sad or euphoric or lustful, and suddenly your pancreas secretes some hormone. Your pancreas? How did you manage to do that with your pancreas? You don’t even know where your pancreas is. Your liver is making an enzyme that wasn’t there before, your spleen is text-messaging something to your thymus gland, blood flow in little capillaries in your ankles has just changed. All from thinking a thought.

You can get hormones from peripheral glands like ovaries, testes, pancreas—but your brain oozing hormones? Preposterous! This seemed not only scientifically implausible but somehow also an unseemly and indecorous thing for your brain to be doing, as opposed to writing sonnets.

(Are you overwhelmed and intimidated by these terms, wondering if you should have bought some Deepak Chopra self-help book instead? Please, don’t even dream of memorizing these names of hormones. The important ones are going to appear so regularly in the coming pages that you will soon be comfortably and accurately slipping them into everyday conversation and birthday cards to favorite cousins. Trust me.)

Never is the maladaptiveness of the stress-response during psychological stress clearer than in the case of the cardiovascular system. You sprint through the restaurant district terrified, and you alter cardiovascular functions to divert more blood flow to your thigh muscles. In such cases, there’s a wonderful match between blood flow and metabolic demand. In contrast, if you sit and think about a major deadline looming next week, driving yourself into a hyperventilating panic, you still alter cardiovascular function to divert more blood flow to your limb muscles. Crazy. And, potentially, eventually damaging.

Establish male monkeys in a social group, and over the course of days to months they’ll figure out where they stand with respect to one another. Once a stable dominance hierarchy has emerged, the last place you want to be is on the bottom: not only are you subject to the most physical stressors but, as will be reviewed in chapter 13 on psychological stress, to the most psychological stressors as well. Such subordinate males show a lot of the physiological indices of chronically turning on their stress-responses. And often these animals wind up with atherosclerotic plaques—their arteries are all clogged up.

Suppose you keep the dominance system unstable by shifting the monkeys into new groups every month, so that all the animals are perpetually in the tense, uncertain stage of figuring out where they stand with respect to everyone else. Under those circumstances, it is generally the animals precariously holding on to their places at the top of the shifting dominance hierarchy who do the most fighting and show the most behavioral and hormonal indices of stress. And, as it turns out, they have tons of atherosclerosis; some of the monkeys even have heart attacks (abrupt blockages of one or more of the coronary arteries).

oft-quoted statement by Elie Wiesel, the Nobel laureate writer and Holocaust survivor: “The opposite of love is not hate. The opposite of love is indifference.”).

In addition, there’s now all that glucose and fatty acid circulating in the bloodstream—oleaginous hoodlums with no place to go, and soon there’s atherosclerotic trouble there as well. The circulating stuff gums up the blood vessels in the kidneys, causing them to fail. The same can occur in the eyes, causing blindness. Blood vessels elsewhere in the body are clogged, causing little strokes in those tissues and, often, chronic pain.

Things now begin to make sense when you consider both the duration of a stressor and the recovery period combined. Suppose that something truly stressful occurs, and a maximal signal to secrete CRH, ACTH, and glucocorticoids is initiated. If the stressor ends after, say, ten minutes, there will cumulatively be perhaps a twelve-minute burst of CRH exposure (ten minutes during the stressor, plus the seconds it takes to clear the CRH afterward) and a two-hour burst of exposure to glucocorticoids (the roughly eight minutes of secretion during the stressor plus the much longer time to clear the glucocorticoids). So the period where glucocorticoid levels are high and those of CRH are low is much longer than the period of CRH levels being high. A situation that winds up stimulating appetite.

The type of stressor is key to whether the net result is hyper- or hypophagia. Take some crazed, maze-running rat of a human. He sleeps through the alarm clock first thing in the morning, total panic. Calms down when it looks like the commute isn’t so bad today, maybe he won’t be late for work after all. Gets panicked all over again when the commute then turns awful. Calms down at work when it looks like the boss is away for the day and she didn’t notice he was late. Panics all over again when it becomes clear the boss is there and did notice. So it goes throughout the day. And how would that person describe his life? “I am like, SO stressed, like totally, nonstop stressed, 24/7.” But that’s not really like totally nonstop stressed. Take a whole body burn. That’s like totally nonstop stressed, 24/7. What this first person is actually experiencing is frequent intermittent stressors. And what’s going on hormonally in that scenario? Frequent bursts of CRH release throughout the day. As a result of the slow speed at which glucocorticoids are cleared from the circulation, elevated glucocorticoid levels are close to nonstop. Guess who’s going to be scarfing up Krispy Kremes all day at work?

It 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. And once again, this makes sense. What does it mean if you have high glucocorticoid levels and low insulin levels in the bloodstream? As we know from chapter 4, you’re in the middle of a stressor. High glucocorticoids and high insulin? This happens during the recovery phase. Pack away those calories to recover from the grassland sprint.

These findings lead to a simple prediction, namely that for the same stressor, if you tend to secrete more glucocorticoids than most, not only are you going to have a bigger appetite post-stressor, you’re going to go apple, preferentially socking away more of those calories in your abdominal fat cells. And that’s precisely what occurs. Epel has studied this in women and men across a range of ages, and she finds that a prolonged glucocorticoid response to novelty is a feature of applish people, not pears.

So with lots of stress, you get cravings for starchy comfort food and you pack it in the abdomen. One final distressing piece of information, based on some fascinating recent work by Mary Dallman from the University of California at San Francisco: consuming lots of those comfort foods and bulking up on abdominal fat are stress-reducers. They tend to decrease the size of the stress-response (both in terms of glucocorticoid secretion and sympathetic nervous system activity). Not only do the Oreos taste good, but by reducing the stress-response, they make you feel good as well.

But why, to add insult to injury, is it so frequently diarrhea when you are truly frightened? Relatively large amounts of water are needed for digestion, to keep your food in solution as you break it down so that it will be easy to absorb into the circulation when digestion is done. As noted, a job of the large intestine is to get that water back, and that’s why your bowels have to be so long—the leftovers slowly inch their way through the large intestine, starting as a soupy gruel and ending up, ideally, as reasonably dry stool. Disaster strikes, run for your life, increase that large intestinal motility, and everything gets pushed through too fast for the water to be absorbed optimally. Diarrhea, simple as that.

So ongoing stress can be closely associated with IBS. Interestingly, traumatic stress early in life (abuse, for example) greatly increases the risk of IBS in adulthood. This implies that childhood trauma can leave an echo of vulnerability, a large intestine that is hyperreactive to stress, long afterward. Animal studies have shown that this occurs.

The Center for Disease Control sent out educational pamphlets to every physician in America, advising them to try to disabuse their patients of the obsolete notion that stress has anything to do with peptic ulcers. Clinicians celebrated at never having again to sit down with their ulcer patients, make some serious eye contact, and ask them how their lives were going.

Now, before I launch into this, I have to issue a warning to anyone who is a parent, or who plans to be a parent, or who had parents. There’s nothing like parenthood to make you really neurotic, as you worry about the consequences of your every act, thought, or omission. I have young children, and here are some of the heinous things that my wife and I have done to irreparably harm them: there was the time we were desperate to placate them about something and allowed them to eat some sugar-bomb breakfast cereal we’d normally ban; then there was the loud concert we went to when our firstborn was a third-trimester fetus, causing him to kick throughout, no doubt in pained protest; and there was the time we messed up with our otherwise ceaseless vigilance and allowed ten seconds of a violent cartoon to show on the television while we fumbled with the Kumbaya-esque video we were attempting to insert. You only want perfection for the ones you love beyond words, so you get nutsy at times.

One final piece of the FOAD story is so intrinsically fascinating that it made me stop thinking like a worried parent for a few minutes and instead I just marveled at biology. 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….

This is precisely what is seen in the Dutch Hunger Winter population, in that their grandchildren are born with lower than expected birth weights. This is seen in other realms as well. Pick some rats at random and feed them on a diet that will make them become obese at the time of pregnancy. As a result, their offspring, despite being fed a normal diet, have an increased risk of obesity. As will their grandkids. Similarly, in humans, having insulin-resistant diabetes while pregnant increases the risk of the disorder in your offspring, after controlling for weight.

Another study that winds up in half the textbooks makes the same point, if more subtly. The subjects of the “experiment” were children reared in two different orphanages in Germany after World War II. Both orphanages were run by the government; thus there were important controls in place—the kids in both had the same general diet, the same frequency of doctors’ visits, and so on. The main identifiable difference in their care was the two women who ran the orphanages. The scientists even checked them, and their description sounds like a parable. In one orphanage was Fräulein Grun, the warm, nurturing mother figure who played with the children, comforted them, and spent all day singing and laughing. In the other was Fräulein Schwarz, a woman who was clearly in the wrong profession. She discharged her professional obligations, but minimized her contact with the children; she frequently criticized and berated them, typically among their assembled peers. The growth rates at the two orphanages were entirely different. Fräulein Schwarz’s kids grew in height and weight at a slower pace than the kids in the other orphanage. Then, in an elaboration that couldn’t have been more useful if it had been planned by a scientist, Fräulein Grun moved on to greener pastures and, for some bureaucratic reason, Fräulein Schwarz was transferred to the other orphanage. Growth rates in her former orphanage promptly increased; those in her new one decreased.

an example that occurred in a British Victorian family. A son, age thirteen, the beloved favorite of the mother, is killed in an accident. The mother, despairing and bereaved, takes to her bed in grief for years afterward, utterly ignoring her other, six-year-old son. Horrible scenes ensue. For example, the boy, on one occasion, enters her darkened room; the mother, in her delusional state, briefly believes it is the dead son—“David, is that you? Could that be you?”—before realizing: “Oh, it is only you.” Growing up, being “only you.” On the rare instances when the mother interacts with the younger son, she repeatedly expresses the same obsessive thought: the only solace she feels is that David died when he was still perfect, still a boy, never to be ruined by growing up and growing away from his mother. The younger boy, ignored (the stern, distant father seemed to have been irrelevant to the family dynamics), seizes upon this idea; by remaining a boy forever, by not growing up, he will at least have some chance of pleasing his mother, winning her love. Although there is no evidence of disease or malnutrition in his well-to-do family, he ceases growing. As an adult, he is just barely five feet in height, and his marriage is unconsummated. And then the chapter informs us that the boy became the author of the much-beloved children’s classic—Peter Pan. J. M. Barrie’s writings are filled with children who didn’t grow up, who were fortunate enough to die in childhood, who came ...

This is actually diagnosed with surprising ease, because of a quirky thing about human males. As soon as they go to sleep and enter REM (rapid eye movement) dream sleep, they get erections. I’ve consulted with Earth’s penis experts, and no one is sure why this should occur, but that’s how it works.*

skulky, filthy, untrustworthy hyenas looking to dart in and steal some of the food. Scavengers! We are invited to heap our contempt on them (a surprising bias, given how few of the carnivorous among us ever wrestle down our meals with our canines). It wasn’t until the Pentagon purchased a new line of infrared night-viewing scopes and decided to unload its old ones on various zoologists that, suddenly, researchers could watch hyenas at night (important, given that hyenas mostly sleep during the day). Turns out that they are fabulous hunters. And you know what happens? Lions, who are not particularly effective hunters, because they are big and slow and conspicuous, spend most of their time keying in on hyenas and ripping off their kills. 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?

The problem with nursing as a contraceptive is how it is done in Western societies.

This is not how most women on earth nurse. A prime example emerged a few years ago in a study of hunter-gatherer Bushmen in the Kalahari Desert of southern Africa (the folks depicted in the movie The Gods Must Be Crazy) Bushman males and females have plenty of intercourse, and no one uses contraceptives, but the women have a child only about every four years. Initially, this seemed easy to explain. Western scientists looked at this pattern and said, “They’re hunter-gatherers: life for them must be short, nasty, and brutish; they must all be starving.” Malnutrition induces cessation of ovulation.

However, when anthropologists looked more closely, they found that the Bushmen were anything but suffering. If you are going to be nonwestemized, choose to be a hunter-gatherer over being a nomadic pastoralist or an agriculturist. The Bushmen hunt and gather only a few hours a day, and spend much of the rest of their time sitting around chewing the fat. Scientists have called them the original affluent society. Out goes the idea that the four-year birth interval is due to malnutrition.

When a hunter-gatherer woman gives birth, she begins to breast-feed her child for a minute or two approximately every fifteen minutes. Around the clock. For the next three years. (Suddenly this doesn’t seem like such a hot idea after all, does it?) The young child is carried in a sling on the mother’s hip so he can nurse easily and frequently. At night, he sleeps near his mother and will nurse every so often without even waking her

This pattern has a fascinating implication. Consider the life history of a hunter-gatherer woman. She reaches puberty at about age thirteen or fourteen (a bit later than in our society). Soon she is pregnant. She nurses for three years, weans her child, has a few menstrual cycles, becomes pregnant again, and repeats the pattern until she reaches menopause. Think about it: over the course of her life span, she has perhaps two dozen periods.

The immune cells aren’t being deactivated—they’re being transferred to the front lines. And a consequence of this is that wounds heal faster.

Thus, early on during exposure to a stressor, glucocorticoids and other stress-responsive hormones transiently activate the immune system, enhancing immune defenses, sharpening them, redistributing immune cells to the scenes of infectious battle. Because of the dangers of the systems overshooting into autoimmunity, more prolonged glucocorticoid exposure begins to reverse these effects, bringing the system back to baseline. And during the pathological scenario of truly major, sustained stressors, immunity is suppressed below baseline.

A repeated theme in this book is how some physiological response to your average, run-of-the-mill mammalian stressor, if too long or too frequent, gets you into trouble.

In retrospective studies, people confronted with an illness are very likely to decide there were stressful events going on. When you rely heavily on retrospective studies with humans, you are likely to get a falsely strong link between stress and disease; and the trouble is, most studies in this field are retrospective

a faster decline and a higher mortality rate occur, on average, among people who have any of the following: (a) a coping style built around denial; (b) minimal social support; (c) a socially inhibited temperament; (d) more stressors, particularly loss of loved ones.

Similar findings emerge from the careful prospective studies of bereavement as a stressor—no link with subsequent cancer.

Some scientists think so. Much of the work in this area has been done with breast cancer, in part because of the prevalence and seriousness of the disease. However, the same pattern has been reported for other cancers as well. The cancer-prone personality, we’re told, is one of repression—emotions held inside, particularly those of anger. This is a picture of an introverted, respectful individual with a strong desire to please—conforming and compliant. Hold those emotions inside and it increases the likelihood that out will come cancer, according to this view.

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.

Furthermore, scientists noted that Chinese veterinarians used acupuncture to do surgery on animals, thereby refuting the argument that the painkilling characteristic of acupuncture was one big placebo effect ascribable to cultural conditioning (no cow on earth will go along with unanesthetized surgery just because it has a heavy investment in the cultural mores of the society in which it dwells).

So stress-induced hyperalgesia is just in your head. On the other hand, so is stress-induced analgesia, just a different part of your head.

Maybe it’s not so much that learning and memory are impaired, as much as the rat being so busy paying attention to that cat smell, or so agitated by it, that it doesn’t make much headway solving whatever puzzle is in front of it.

There are also findings (although fewer in number) showing that stress disrupts something called “executive function.” This is a little different from memory. Rather than this being the cognitive realm of storing and retrieving facts, this concerns what you do with the facts—whether you organize them strategically, how they guide your judgments and decision making. This is the province of a part of the brain called the prefrontal cortex.

In contrast, the volume losses in PTSD and major depression appear to be something approaching permanent, in that the loss persists in the former case decades after the trauma, and, in the latter, years to decades after the depression has been gotten under control with medication. So in those cases, the volume loss in the hippocampus probably can’t be due to shriveling processes of neurons, given that the shriveling can reverse.

Consider how bizarre and maladaptive this is. Lion chases you; you secrete glucocorticoids in order to divert energy to your thigh muscles—great move. Go on a blind date, secrete glucocorticoids in order to divert energy to your thigh muscles—probably irrelevant. Have a grand mal seizure, secrete glucocorticoids in order to divert energy to your thigh muscles—and make the brain damage worse. This is as stark a demonstration as you can ask for that a stress-response is not always what you want your body to be having.

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.