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 stress-response can be mobilized not only in response to physical or psychological insults, but also in expectation of them.

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

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.

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.

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.

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.

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.

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. In some cases, the brain triggers the release of pituitary hormone X through the action of a single releasing hormone. Sometimes it halts the release of pituitary hormone Y by releasing a single inhibiting hormone. In some cases, a pituitary hormone is controlled by the coordination of both a releasing and an inhibiting hormone from the brain--dual control.

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.

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

Stress can promote plaque formation by increasing the odds of blood vessels being damaged and inflamed, and by increasing the likelihood that circulating crud (platelets, fat, cholesterol, and so on) sticks to those inflamed injury sites.

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). Therefore, the length of time between heartbeats tends to be shorter when you're inhaling than exhaling. But what if chronic stress has blunted the ability of your parasympathetic nervous system to kick the vagus nerve into action? When you exhale, your heart won't slow down, won't increase the time intervals between beats. Cardiologists use sensitive monitors to measure interbeat intervals. 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.

The risk of cardiovascular disease is increased by hostility, a Type-A personality, and by clinical depression.

During stress, glucocorticoids act on fat cells throughout the body to make them less sensitive to insulin. 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.

Tricks that sexual therapists advise--if you are close to ejaculating and don't want to yet, take a deep breath. Expanding the chest muscles briefly triggers a parasympathetic volley that defers the shift from parasympathetic to sympathetic.

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.

The impact of social relationships on life expectancy appears to be at least as large as that of variables such as cigarette smoking, hypertension, obesity, and level of physical activity.

Collectively, we have, with the exception of two studies concerning one type of cancer, no overall suggestion that stress increases the risk of cancer in humans. What if your cancer has been cured? Does stress increase the risk of it coming back? The handful of studies on this subject don't suggest that there's a connection--a few say yes, an equal number, no.

Acupuncture stimulates the release of large quantities of endogenous opioids, for reasons no one really understands. The best demonstration of this is what is called a subtraction experiment: block the activity of endogenous opioids by using a drug that blocks the opiate receptor (most commonly a drug called naloxone). When such a receptor is blocked, acupuncture no longer effectively dulls the perception of pain. Stress releases opioids as well.

There is some evidence that DHEA serves as an "anti-stress" hormone, blocking the actions of glucocorticoids, and that it can have some beneficial effects in aged populations.

People who are socially isolated have overly active sympathetic nervous systems. Given the likelihood that this will lead to higher blood pressure and more platelet aggregation in their blood vessels, they are more likely to have heart disease--two to five times as likely, as it turns out. And once they have the heart disease, they are more likely to die at a younger age.

Predictability makes stressors less stressful. In the absence of any stressor, loss of predictability triggers a stress-response.

Predictive information lets us know what internal coping strategy is likely to work best during a stressor.

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. The control element is more powerful than the demand one--low demand and low control is more damaging to one's health than high demand and high control.

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 theme found in the activities and statements of many scions of great fortunes, who regret the contingency-free nature of their lives, without purpose or striving.

Given the same degree of disruption of allostasis, a perception that events are improving helps tremendously. It's not just the external reality; it's the meaning you attach to it.

Stress-responses can be modulated or even caused by psychological factors, including loss of outlets for frustration and of social support, a perception of things worsening, and under some circumstances, a loss of control and of predictability.

With the same external stressors, the more that someone has an internal locus of control--the perception that they are the masters of their own destiny--, the less the likelihood of a depression.

Psychological approaches to depression give us some insight into the nature of the disease. According to one school, it is a state brought about by pathological overexposure to loss of control and outlets for frustration. In another psychological view, the Freudian one, it is the internalized battle of ambivalences, aggression turned inward. These views contrast with the more biological ones--that depression is a disorder of abnormal neurotransmitter levels, abnormal communication between certain parts of the brain, abnormal hormone ratios, genetic vulnerability. Stress is the unifying theme that pulls together these disparate threads of biology and psychology.

If you block the sympathetic nervous system in someone who has just suffered a major trauma (with a beta-blocker), you decrease the odds of the person developing post-traumatic stress disorder. What's the rationale? Decrease the sympathetic signal to the amygdala, and the amygdala is less likely to decide that this is an event that should provoke wild arousal forever after.

"If you want to know if the elephant at the zoo has a stomachache, don't ask the veterinarian, ask the cage cleaner." People who clean up messes become attuned to circumstances that change the amount of mess there is.

Humans with more of an internalized locus of control are more resistant in experimental models of learned helplessness.

Maybe the goal isn't to maximize the contrast between a low baseline and a high level of activation. Maybe the idea is to have both simultaneously. Huh? Maybe the goal would be for your baseline to be something more than the mere absence of activation, a mere default, but to instead be an energized calm, a proactive choice. And for the ceiling to consist of some sort of equilibrium and equanimity threading through the crazed arousal. I have felt this a few times playing soccer, inept as I am at it, where there's a moment when, successful outcome or not, every physiological system is going like mad, and my body does something that my mind didn't even dream of, and the two seconds when that happened seemed to take a lot longer than it should have. But this business about the calm amid the arousal isn't just another way of talking about "good stress" (a stimulating challenge, as opposed to a threat). Even when the stressor is bad and your heart is racing in crisis, the goal should be to somehow make the fraction of a second between each heartbeat into an instant that expands in time and allows you to regroup.

Those who cope with stress successfully tend to seek control in the face of present stressors but do not try to control things that have already come to pass. They do not try to control future events that are uncontrollable and do not try to fix things that are not broken or that are broken beyond repair. When faced with the large wall of a stressor, it is great if there emerges one singular solution that makes the wall crumble. But often, a solution instead will be a series of footholds of control, each one small but still capable of giving support, that will allow you to scale the wall.

"In the face of strong winds, let me be a blade of grass. In the face of strong walls, let me be a gale of wind." Sometimes, coping with stress consists of blowing down walls. But sometimes it consists of being a blade of grass, buffeted and bent by the wind but still standing when the wind is long gone.