Robert Sapolsky’s Why Zebra’s Don’t Get Ulcers

img_0084Before tackling Robert Sapolsky’s new book Behave: The Biology of Humans at Our Best and Worst, I decided to read Sapolsky’s earlier, well-regarded book Why Zebra’s Don’t Get Ulcers. I have been a fan of Sapolsky’s for some time, largely through his appearance on various podcasts. (This discussion with Sam Harris is excellent.)

Why Zebra’s Don’t Get Ulcers is a wonderful book. Sapolsky is a great writer, and the science is interesting. That Sapolsky did not sugarcoat the introduction to every chapter with a cute story, as seems to be a common formula today, made the book a pleasant contrast to a lot of my recent reading.

The core theme of the book is that chronic stress is bad for your health. It can lead to cardiovascular disease, destroy your sleep, age you faster, and so on. The one positive (relative to common beliefs) is that stress probably doesn’t cause cancer (with the possible exception of colon cancer).

The story linking stress with these health problems largely revolves around the hormones that trigger the stress response. I’ll give a quick synopsis of this story, as it helps give context to some of the snippets below.

When the stressor first arises, CRH (corticotropin releasing hormone) is released from the hypothalamus in the brain. CRH helps to turn on the sympathetic nervous system, with the nerve endings of the sympathetic nervous system releasing adrenaline (called epinephrine through the book). This all leads to increased heart rate, vigilance and arousal. It triggers the cessation of many bodily functions, such as digestion, repair and reproductive processes, and suppresses immunity, mobilising the body’s resources to solve the stressor at hand.

Fast forward 15 seconds, and the CRH has triggered the pituitary at the base of the brain to release ACTH (also known as corticotropin). A few minutes later the ACTH in turn triggers the release of glucocorticoids by the adrenal gland. The glucocorticoids increase the stress response, further arousing the sympathetic nervous system and raising circulating glucose. The glucocorticoids are also involved in recovery and the preparation for the next stressor. For instance, they stimulate appetite.

Many of the costs of stress arise through the actions of these hormones when the stress is intermittent or chronic. CRH is cleared from the body a couple of minutes after the end of the stressor. It can take hours for glucocorticoids to be cleared. Continued intermittent or chronic stressors results in permanently elevated glucocorticoid levels, subjecting the body to a stress response without pause. For instance, the stress response makes the heart work harder. If you are in chronic stress, this increased work effort is constant, leading to high blood pressure, and wearing out your blood vessels.

There are a raft of other hormones and processes involved in the stress response, each with their own roles, costs and benefits, but this basic picture, particularly the cost of ongoing high levels of glucocorticoids, forms the books central thread.

Although this sounds like a somewhat mechanical process, an important theme in the book is that the cost of stress is not just a mechanical equation, whereby stress causes a bodily response with various costs. The book balances a reductive view of biology, in which you can trace everything back to physical factors such as bacteria, viruses, genes, hormones and so on, with another view that is more psychologically grounded. In that latter view, stress can be purely psychological, affected by someone’s sense of control and so on.

The one part of the book that I found mildly unsatisfying was the chapter on the link between stress, poverty and health. Naturally, poverty and poor health are closely linked, with poverty associated with greater stress. Sapolsky asks about direction of causality: does poverty harm health, or does poor health lead to poverty. But (as he does in some other chapters), Sapolsky does not delve deeply into whether there might be other causal factors. I felt that that chapter deserves another book.

More generally, I don’t have the subject expertise to critique the book, but I highlighted a lot of interesting passages. Below is a selection.

On sex differences in stress response:

Taylor argues convincingly that the physiology of the stress-response can be quite different in females, built around the fact that in most species, females are typically less aggressive than males, and that having dependent young often precludes the option of flight. Showing that she can match the good old boys at coming up with a snappy sound bite, 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.

A few critics of Taylor’s influential work have pointed out that sometimes the stress-response in females can be about fight-or-flight, rather than affiliation. For example, females are certainly capable of being wildly aggressive (often in the context of protecting their young), and often sprint for their lives or for a meal (among lions, for example, females do most of the hunting). Moreover, sometimes the stress-response in males can be about affiliation rather than fight-or-flight. This can take the form of creating affiliative coalitions with other males or, in those rare monogamous species (in which males typically do a fair amount of the child care), some of the same tending and befriending behaviors as seen among females. 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.

On stress making us both eat more and less:

The official numbers are that stress makes about two-thirds of people hyperphagic (eating more) and the rest hypophagic. Weirdly, when you stress lab rats, you get the same confusing picture, where some become hyperphagic, others hypophagic. So we can conclude with scientific certainty that stress can alter appetite. Which doesn’t teach us a whole lot, since it doesn’t tell us whether there’s an increase or decrease. …

The confusing issue is that one of the critical hormones of the stress-response stimulates appetite, while another inhibits it. … CRH inhibits appetite, glucocorticoids do the opposite. Yet they are both hormones secreted during stress. Timing turns out to be critical. …

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. In contrast, suppose the stressor lasts for days, nonstop. In other words, days of elevated CRH and glucocorticoids, followed by a few hours of high glucocorticoids and low CRH, as the system recovers. The sort of setting where the most likely outcome is suppression of 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. … 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.

On the link between the brain and immunity:

The evidence for the brain’s influence on the immune system goes back at least a century, dating to the first demonstration that if you waved an artificial rose in front of someone who is highly allergic to roses (and who didn’t know it was a fake), they’d get an allergic response. … [T]he study that probably most solidified the link between the brain and the immune system used a paradigm called 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. … The two researchers experimented with a strain of mice that spontaneously develop disease because of overactivity of their immune systems. Normally, the disease is controlled by treating the mice with an immunosuppressive drug. Ader and Cohen showed that by using their conditioning techniques, they could substitute the conditioned stimulus for the actual drug—and sufficiently alter immunity in these animals to extend their life spans.

Does acupuncture rely on a placebo effect?

[S]cientists 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).

On the anticipatory stress when you set an early alarm:

In the study, one group of volunteers was allowed to sleep for as long as they wanted, which turned out to be until around nine in the morning. As would be expected, their stress hormone levels began to rise around eight. How might you interpret that? These folks had enough sleep, happily restored and reenergized, and by about eight in the morning, their brains knew it. Start secreting those stress hormones to prepare to end the sleep. But the second group of volunteers went to sleep at the same time but were told that they would be woken up at six in the morning. And what happened with them? At five in the morning, their stress hormone levels began to rise. This is important. Did their stress hormone levels rise three hours earlier than the other group because they needed three hours less sleep? Obviously not. … Their brains were feeling that anticipatory stress while sleeping, demonstrating that a sleeping brain is still a working brain.

On the importance of having outlets for stress, even if that outlet is someone else:

An organism is subjected to a painful stimulus, and you are interested in how great a stress-response will be triggered. The bioengineers had been all over that one, mapping the relationship between the intensity and duration of the stimulus and the response. But this time, when the painful stimulus occurs, the organism under study can reach out for its mommy and cry in her arms. Under these circumstances, this organism shows less of a stress-response. …

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 subject of one experiment is a rat that receives mild electric shocks (roughly equivalent to the static shock you might get from scuffing your foot on a carpet). Over a series of these, the rat develops a prolonged stress-response: its heart rate and glucocorticoid secretion rate go up, for example. For convenience, we can express the long-term consequences by how likely the rat is to get an ulcer, and in this situation, the probability soars. In the next room, a different rat gets the same series of shocks—identical pattern and intensity; its allostatic balance is challenged to exactly the same extent. But this time, whenever the rat gets a shock, it can run over to a bar of wood and gnaw on it. The rat in this situation is far less likely to get an ulcer. You have given it an outlet for frustration. Other types of outlets work as well—let the stressed rat eat something, drink water, or sprint on a running wheel, and it is less likely to develop an ulcer. …

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.

On how predictability can make stressors less stressful:

During the onset of the Nazi blitzkrieg bombings of England, London was hit every night like clockwork. Lots of stress. In the suburbs the bombings were far more sporadic, occurring perhaps once a week. Fewer stressors, but much less predictability. There was a significant increase in the incidence of ulcers during that time. Who developed more ulcers? The suburban population. (As another measure of the importance of unpredictability, by the third month of the bombing, ulcer rates in all the hospitals had dropped back to normal.)

On the link between low SES and poor health – it is more about someone’s beliefs than their actual level of poverty:

[T]he SES/ health gradient is not really about a distribution that bottoms out at being poor. It’s not about being poor. It’s about feeling poor, which is to say, it’s about feeling poorer than others around you. …

Instead of just looking at the relationship between SES and health, Adler looks at what health has to do with what someone thinks and feels their SES is—their “subjective SES.” Show someone a ladder with ten rungs on it and ask them, “In society, where on this ladder would you rank yourself in terms of how well you’re doing?” Simple. First off, if people were purely accurate and rational, the answers across a group should average out to the middle of the ladder’s rungs. But cultural distortions come in—expansive, self-congratulatory European-Americans average out at higher than the middle rung (what Adler calls her Lake Wobegon Effect, where all the children are above average); in contrast, Chinese-Americans, from a culture with less chest-thumping individualism, average out to below the middle rung. …

Amazingly, it is at least as good a predictor of these health measures as is one’s actual SES, and, in some cases, it is even better.

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