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.

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.

Our human experience is replete with psychological stressors, a far cry from the physical world of hunger, injury, blood loss, or temperature extremes.

The body doesn’t pull off all this regulatory complexity only to correct some set point that has gone awry. It can also make allostatic changes in anticipation of a set point that is likely to go awry. And thus we hark back to the critical point of a few pages back—we don’t get stressed being chased by predators.

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.

If the lion’s on your tail, two steps behind you, worry about ovulating or growing antlers or making sperm some other time. During stress, growth and tissue repair is curtailed, sexual drive decreases in both sexes; females are less likely to ovulate or to carry pregnancies to term, while males begin to have trouble with erections and secrete less testosterone.

With sufficiently sustained stress, our perception of pain can become blunted.

Finally, during stress, shifts occur in cognitive and sensory skills. Suddenly certain aspects of memory improve,

Collectively, the stress-response is ideally adapted for that zebra or lion. Energy is mobilized and delivered to the tissues that need them; long-term building and repair projects are deferred until the disaster has passed. Pain is blunted, cognition sharpened.

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.

The preceding pages should allow you to begin to appreciate the two punch lines of this book: The first is that 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.

If you repeatedly turn on the stress-response, or if you cannot turn off the stress-response at the end of a stressful event, the stress-response can eventually become damaging. A large percentage of what we think of when we talk about stress-related diseases are disorders of excessive stress-responses.

Have a huge meal, sit there bloated and happily drowsy, and the parasympathetic is going like gangbusters. Sprint for your life across the savanna, gasping and trying to control the panic, and you’ve turned the parasympathetic component down.

If a neuron (a cell of the nervous system) secretes a chemical messenger that travels a thousandth of an inch and causes the next cell in line (typically, another neuron) to do something different, that messenger is called a neurotransmitter. Thus, 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.

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.

Outline of the control of glucocorticoid secretion. A stressor is sensed or anticipated in the brain, triggering the release of CRH (and related hormones) by the hypothalamus. These hormones enter the private circulatory system linking the hypothalamus and the anterior pituitary, causing the release of ACTH by the anterior pituitary. ACTH enters the general circulation and triggers the release of glucocorticoids by the adrenal gland.

The principal such releaser is called CRH (corticotropin releasing hormone), while a variety of more minor players synergize with CRH.* Within fifteen seconds or so, CRH triggers the pituitary to release the hormone ACTH (also known as corticotropin). After ACTH is released into the bloodstream, it reaches the adrenal gland and, within a few minutes, triggers glucocorticoid release. Together, glucocorticoids and the secretions of the sympathetic nervous system (epinephrine and norepinephrine) account for a large percentage of what happens in your body during stress. These are the workhorses of the stress-response.

In addition, in times of stress your pancreas is stimulated to release a hormone called glucagon. Glucocorticoids, glucagon, and the sympathetic nervous system raise circulating levels of the sugar glucose. As we will see, these hormones are essential for mobilizing energy during stress. Other hormones are activated as well. The pituitary secretes prolactin, which, among other effects, plays a role in suppressing reproduction during stress. Both the pituitary and the brain also secrete a class of endogenous morphine-like substances called endorphins and enkephalins, which help blunt pain perception, among other things. Finally, the pituitary also secretes vasopressin, also known as antidiuretic hormone, which plays a role in the cardiovascular stress-response.

Just as some glands are activated in response to stress, various hormonal systems are inhibited during stress. The secretion of various reproductive hormones such as estrogen, progesterone, and testosterone is inhibited. Hormones related to growth (such as growth hormone) are also inhibited, as is the secretion of insul...

And the fact that oxytocin is secreted during stress in females supports the idea that responding to stress may not just consist of preparing for a mad dash across the savanna, but may also involve feeling a pull toward sociality.

Some glucocorticoid actions do help mediate the stress-response. Others help mediate the recovery from the stress-response. As will be described in chapter 8, this probably has important implications for a number of autoimmune diseases. And some glucocorticoid actions prepare you for the next stressor. As will be discussed in chapter 13, this is critical for understanding the ease with which anticipatory psychological states can trigger glucocorticoid secretion.

The sympathetic nervous system and glucocorticoids play a role in the response to virtually all stressors. But the speed and magnitudes of the sympathetic and glucocorticoid branches can vary depending on the stressor, and not all of the other endocrine components of the stress-response are activated for all stressors. The orchestration and patterning of hormone release tend to vary at least somewhat from stressor to stressor, with there being a particular hormonal “signature” for a particular stressor.

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

In some cases, the stress signature sneaks in through the back door. Two stressors can produce identical profiles of stress hormone release into the bloodstream. So where’s the signature that differentiates them? Tissues in various parts of the body may be altered in their sensitivity to a stress hormone in the case of one stressor, but not the other.

Glucocorticoids add to this as well, both by activating neurons in the brain stem that stimulate sympathetic arousal, and by enhancing the effects of epinephrine and norepinephrine on heart muscle. You also want to increase the force with which your heart beats. This involves a trick with the veins that return blood to your heart. Your sympathetic nervous system causes them to constrict, to get more rigid. And that causes the returning blood to blast through those veins with more force. Blood returns to your heart with more force, slamming into your heart walls, distending them more than usual…and those heart walls, like a stretched rubber band, snap back with more force.

Arteries are relaxed—dilated—that lead to your muscles, increasing blood flow and energy delivery there. At the same time, there is a dramatic decrease in blood flow to nonessential parts of your body, like your digestive tract and skin

you decrease blood flow to your kidneys and, in addition, your brain sends a message to the kidneys: stop the process, reabsorb the water into the circulatory system. This is accomplished by the hormone vasopressin (known as antidiuretic hormone for its ability to block diuresis, or urine formation), as well as a host of related hormones that regulate water balance.

In the last few years, it is becoming clear that the amount of damaged, inflamed blood vessels is a better predictor of cardiovascular trouble than is the amount of circulating crud.

How can you measure the amount of inflammatory damage? A great marker is turning out to be something called C-reactive protein (CRP). It is made in the liver and is secreted in response to a signal indicating an injury. It migrates to the damaged vessel where it helps amplify the cascade of inflammation that is developing. Among other things, it helps trap bad cholesterol in the inflamed aggregate.

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

But tear it loose now, form what is called a thrombus, and that mobile hairball can now lodge in a much smaller blood vessel, clogging it completely. Clog up a coronary artery and you’ve got a myocardial infarct, a heart attack (and this thrombus route accounts for the vast majority of heart attacks). Clog up a blood vessel in the brain and you have a brain infarct (a stroke).

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).

Large amounts of variability (that is to say, short interbeat intervals during inhalation, long during exhalation) mean you have strong parasympathetic tone counteracting your sympathetic tone, a good thing. Minimal variability means a parasympathetic component that has trouble putting its foot on the brake. This is the marker of someone who not only turns on the cardiovascular stress-response too often but, by now, has trouble turning it off.

complex food matter is broken down into its simplest parts (molecules): amino acids (the building blocks of protein), simple sugars like glucose (the building blocks of more complex sugars and of starches [carbohydrates]), and free fatty acids and glycerol (the constituents of fat).

The hormone that stimulates the transport and storage of these building blocks into target cells is insulin. Insulin is this optimistic hormone that plans for your metabolic future.

Your body reverses all of the storage steps through the release of the stress hormones glucocorticoids, glucagon, epinephrine, and norepinephrine. These cause triglycerides to be broken down in the fat cells and, as a result, free fatty acids and glycerol pour into the circulatory system. The same hormones trigger the degradation of glycogen to glucose in cells throughout the body, and the glucose is then flushed into the bloodstream. These hormones also cause protein in non-exercising muscle to be converted back to individual amino acids.

The stored nutrients have now been converted into simpler forms. Your body makes another simplifying move. 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. The liver can also generate new glucose, a process called gluconeogenesis, and this glucose is now readily available for energy during the disaster.

In the same way, every time you store energy away from the circulation and then return it, you lose a fair chunk of the potential energy. It takes energy to shuttle those nutrients in and out of the bloodstream, to power the enzymes that glue them together (into proteins, triglycerides, and glycogen) and the other enzymes that then break them apart, to fuel the liver during that gluconeogenesis trick. In effect, you are penalized if you activate the stress-response too often: you wind up expending so much energy that, as a first consequence, you tire more readily—just plain old everyday fatigue.

As is well understood, there is “bad” cholesterol, also known as low-density lipoprotein-associated cholesterol (LDL) and “good” cholesterol (high-density lipoprotein-associated cholesterol, HDL). LDL-cholesterol is the type that gets added to an atherosclerotic plaque, whereas HDL-cholesterol is cholesterol that has been removed from plaques and is on its way to be degraded in the liver.

The first is known as juvenile diabetes (or type 1, insulin-dependent diabetes). For reasons that are just being sorted out, in some people the immune system decides that the cells in the pancreas that secrete insulin are, in fact, foreign invaders and attacks them (such “autoimmune” diseases will be discussed in chapter 8). This destroys those cells, leaving the person with little ability to secrete insulin.

during stress, glucocorticoids act on fat cells throughout the body to make them less sensitive to insulin, just in case there’s some still floating around. Fat cells then release some newly discovered hormones that get other tissues, like muscle and liver, to stop responding to insulin as well. Stress promotes insulin resistance.

In adult-onset diabetes (type 2, non-insulin-dependent diabetes), the trouble is not too little insulin, but the failure of the cells to respond to insulin. Another name for the disorder is thus insulin-resistant diabetes.

The overstuffed fat cells even release hormones that trigger other fat cells and muscle into becoming insulin resistant. Do the cells now starve? Of course not, the abundant amounts of fat stored in them was the source of the trouble in the first place. The body gets into trouble because of all that circulating glucose and fatty acids, damaging blood vessels. Same old problem. And if the adult-onset diabetes goes on for a while, an additional, miserable development can occur. Your body has become insulin-resistant. Your pancreas responds by secreting even more insulin than usual. You’re still resistant. So the pancreas secretes even more. Back and forth, your pancreas pumping out ever higher levels of insulin, trying to be heard. Eventually, this burns out the insulin-secreting cells in the pancreas, actually destroying them. So you finally get your adult-onset diabetes under control, thanks to losing weight and exercising, and you discover you’ve now got juvenile diabetes, thanks to that damage to your pancreas.

And if the adult-onset diabetes goes on for a while, an additional, miserable development can occur. Your body has become insulin-resistant. Your pancreas responds by secreting even more insulin than usual. You’re still resistant. So the pancreas secretes even more. Back and forth, your pancreas pumping out ever higher levels of insulin, trying to be heard. Eventually, this burns out the insulin-secreting cells in the pancreas, actually destroying them. So you finally get your adult-onset diabetes under control, thanks to losing weight and exercising, and you discover you’ve now got juvenile diabetes, thanks to that damage to your pancreas.

Make a list of some of the things that can go wrong from the last two chapters: elevated insulin levels in the blood. Elevated glucose levels. Elevated systolic and diastolic blood pressure. Insulin resistance. Too much LDL-cholesterol. Too little HDL. Too much fat or cholesterol in the blood. Suffer from a subset of these, and you’ve got Metabolic syndrome

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? So a big reason why most of us become hyperphagic during stress is our westernized human capacity to have intermittent psychological stressors throughout the day. The type of stressor is a big factor.

So we differ as to whether stress stimulates or inhibits our appetite, and this has something to do with the type and pattern of stressors, how reactive our glucocorticoid system is to stress, and whether eating is normally something that we keep a tight, superegoish lid on.

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.

Match them for weight, and it’s the apples who are at risk for metabolic and cardiovascular disease. Among other reasons, this is probably because fat released from abdominal fat cells more readily finds its way to the liver (in contrast to fat from gluteal fat stores, which gets dispersed more equally throughout the body), where it is converted into glucose, setting you up for elevated blood sugar and insulin resistance. 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.

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).