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The Heavy Cost of Chronic Stress

December 17, 2002

By ERICA GOODE

In this season of bickering relatives and whining children,

of overcrowded department stores and unwritten Christmas

cards, it is instructive to consider the plight of the

Pacific salmon.

As the fish leap, flop and struggle upstream to spawn,

their levels of cortisol, a potent stress hormone, surge,

providing energy to fight the current. But the hormone also

leads the salmon to stop eating. Their digestive tracts

wither away. Their immune systems break down. And after

laying their eggs, they die of exhaustion and infection,

their bodies worn out by the journey.

Salmon cannot help being stressed out. They are programmed

to die, their systems propelled into overdrive by

evolutionary design.

Humans, on the other hand, are usually subject to stresses

of their own making, the chronic, primarily psychological,

pressures of modern life. Yet they also suffer consequences

when the body's biological mechanisms for handling stress

go awry.

Prolonged or severe stress has been shown to weaken the

immune system, strain the heart, damage memory cells in the

brain and deposit fat at the waist rather than the hips and

buttocks (a risk factor for heart disease, cancer and other

illnesses), said Dr. Bruce S. McEwen, director of the

neuroendocrinology laboratory at the Rockefeller University

and the author of a new book, " The End of Stress as We Know

It. " Stress has been implicated in aging, depression, heart

disease, rheumatoid arthritis and diabetes, among other

illnesses.

Researchers have known for many decades that physical

stress takes a toll on the body. But only relatively

recently have the profound effects of psychological stress

on health been widely acknowledged. Two decades ago, many

basic scientists scoffed at the notion that mental state

could affect illness. The link between mind and body was

considered murky territory, best left to psychiatrists.

But in the last decade, researchers have convincingly

demonstrated that psychological stress can increase

vulnerability to disease and have begun to understand how

that might occur.

" If you would have said to me back in 1982 that stress

could modulate how the immune system worked, I would have

said, `Forget about it,' " said Dr. Glaser, an

immunologist at Ohio State University.

The more researchers have learned, the clearer it has

become that stress may be a thread tying together many

illnesses that were previously thought to be unrelated.

" What used to be thought of as pathways that led pretty

explicitly to one particular disease outcome can now be

seen as leading to a whole lot of different outcomes, " said

Dr. M. Sapolsky, a professor of neurology at

Stanford.

Central to this new understanding is a novel conception of

stress, developed by Dr. McEwen, who has been studying the

subject for more than three decades. According to his

model, it is not stress per se that is harmful. Rather, the

problems associated with stress result from a complicated

interaction between the demands of the outside world and

the body's capacity to manage potential threats.

That capacity can be influenced by heredity and childhood

experience; by diet, exercise and sleep patterns; by the

presence or absence of close personal relationships; by

income level and social status; and by the piling on of

normal stresses to the point that they overload the system.

In moderate amounts, the scientists argue, stress can be

benign, even beneficial, and most people are equipped to

deal with it.

Preparing to give a speech, take a test or avoid a speeding

car, the body undergoes an elaborate series of adjustments.

Physiological processes essential in mobilizing a response

- the cardiovascular system, the immune system, the

endocrine glands and brain regions involved in emotion and

memory - are recruited into action. Nonessential functions

like reproduction and digestion are put off till later.

Adrenaline, and later cortisol, both stress hormones

secreted by the adrenal glands, flood the body. Heart rate

and blood pressure rise, respiration quickens, oxygen flows

to the muscles, and immune cells prepare to rush to the

site of an injury.

When the speech is delivered, the test taken or the car

avoided, another complex set of adjustments calms things

down, returning the body to normal.

This process of " equilibrium through change " is called

allostasis, and it is essential for survival. But it was

developed, Dr. McEwen and Dr. Sapolsky point out, for the

dangers humans might have encountered in a typical day on

the savannah, the sudden appearance of a lion, for example,

or a temporary shortage of antelope meat.

Blaring car alarms, controlling bosses, two-career

marriages, six-mile traffic jams and rude salesclerks were

simply not part of the plan.

When stress persists for too long or becomes too severe,

Dr. McEwen said, the normally protective mechanisms become

overburdened, a condition that he refers to as allostatic

load. The finely tuned feedback system is disrupted, and

over time it runs amok, causing damage.

Work that Dr. McEwen and his colleagues have conducted with

rats nicely illustrates this wear-and-tear effect. In the

studies, the rats were placed in a small compartment, their

movement restricted for six hours a day during their normal

resting time. The first time the rats were restrained, Dr.

McEwen said, their cortisol levels rose as their stress

response moved into full gear. But after that, their

cortisol production switched off earlier each day as they

became accustomed to the restraint.

That might have been the end of the story. But the

researchers also found that at 21 days, the rats began to

show the effects of chronic stress. They grew anxious and

aggressive. Their immune systems became slower to fight off

invaders. Nerve cells in the hippocampus, a brain region

involved in memory, atrophied. The production of new

hippocampal neurons stopped.

Dr. Sheldon Cohen, a professor of psychology at Carnegie

Mellon University, has found that people respond much the

same way. Among volunteers inoculated with a cold virus,

those who reported life stresses that continued for more

than one month like unemployment or family problems were

more likely to develop colds than those who reported stress

lasting less than a month. The longer the stress persisted,

the greater the risk of illness.

Allostatic load is often made worse, Dr. McEwen said, by

how people respond to stress, eating fatty foods, staying

late at work, avoiding the treadmill or drinking to excess.

" The fact is that we're now living in a world where our

systems are not allowed a chance to rest, to go back to

base line, " he said. " They're being driven by excess

calories, by inadequate sleep, by lack of exercise, by

smoking, by isolation or frenzied competition. "

The Chemistry

Shrinking Cells,

Turned-Off Responses

Doctors sometimes dismiss stress-related complaints as " all

in the patient's head. " In a sense, they are right. The

brain, specifically the amygdala, detects the first signs

of danger, as demonstrated in now-classic studies by Dr.

ph LeDoux of New York University. Other brain areas

evaluate the threat's importance, decide how to respond and

remember when and where the danger occurred, increasing the

chances of avoiding it next time.

So it is not surprising that when the stress system is

derailed, the brain is a target for damage. A decade of

research has demonstrated that sustained stress and the

resulting overproduction of cortisol can have chilling

effects on the hippocampus, a horseshoe-shaped brain

structure intimately involved in memory formation.

Scientists say they believe that the hippocampus plays an

active role in registering not only events, but also their

context, an important task in the face of danger. In

stressful situations, the hippocampus also helps turn off

the stress response after the threat has subsided.

But high levels of cortisol, studies have shown, can shrink

nerve cells in the hippocampus and halt the creation of new

hippocampal neurons. These changes are associated with

aging and memory problems. Some evidence also links a

smaller hippocampus with post-traumatic stress disorder,

depression and sexual abuse in childhood, though the

meaning of this size difference is still being debated.

Like other hormones, cortisol normally rises and falls with

daily rhythms, its production higher in the morning and

lower in the evening. Prolonged or severe stress appears to

disrupt the cycle. Chronically stressed people sometimes

have higher base line cortisol levels and produce too much

or too little of it at the wrong times.

One result, recent studies indicate, is that fat is

deposited at the abdomen rather than the hips or the

buttocks. One of cortisol's primary functions is to help

mobilize energy in times of acute stress by releasing

glucose into the blood. But when cortisol remains

chronically elevated, it acts, along with high insulin

levels, to send fat into storage at the waist. This makes

sense if a famine looms. But it is bad news for anyone who

wants to minimize the risk of heart disease, cancer and

other illnesses.

Studies have shown that excess cortisol secretion in

animals increases visceral fat. And Dr. Elissa S. Epel at

the University of California at San Francisco has found

that even in slender women, stress, cortisol and belly fat

seem to go together.

The notion that being stressed makes people sick is a

popular one, and most people subscribe to some version of

it. Come down with the flu in the midst of a messy divorce

or a frantic period at the office, and someone is bound to

blame stress.

But it was not until the 1980's and early 90's that

scientists began to discover the mechanisms that might lie

behind the mind and body link. Investigators uncovered

nerves that connect the brain with the spleen and thymus,

organs important in immune responses, and they established

that nerve cells could affect the activity of

infection-fighting white blood cells.

Scientists also found that cytokines, proteins produced by

immune cells, could influence brain processes. Among other

things, the proteins appeared able to activate the second

major phase of the stress response, the so-called

hypothalamic-pituitary-adrenal, or H.P.A., axis. In this

chemical sequence, the hypothalamus, situated in the

forebrain, dispatches chemical signals to the pituitary,

which in turn secretes the stress hormone ACTH, prompting

the adrenal glands to produce cortisol.

Much remains unknown about how the brain, the endocrine

system and the immune system interact, and some of what is

known is not well understood. For example, high levels of

cortisol have long been known to shut off the production

and action of cytokines, which initiate the immune

response. At normal levels, cortisol can enhance immunity

by increasing the production of inflammation-fighting

cytokines. Yet in some cases, it seems, cortisol does not

properly shut down the immune system under stress, allowing

the continued production of cytokines that promote

inflammation. These cytokines have been linked to heart

disease, depression, stroke and other illnesses.

Still, scientists can watch stress hammer away at the

immune system in the laboratory. Dr. Glaser of Ohio State

and his wife, Dr. Janice Kiecolt-Glaser, found that small

wounds took an average of nine days longer to heal in women

who cared for patients with Alzheimer's disease than in

women who were not under similar stress. In another study,

arguments between husbands and wives were accompanied by

increases in stress hormones and immunological changes over

a 24-hour period.

Stress also seems to make people more likely to contract

some infectious illnesses. Dr. Cohen of Carnegie Mellon has

spent years inoculating intrepid volunteers with cold and

influenza viruses, and his findings offer strong evidence

that stressed people are more likely to become infected and

had more severe symptoms after becoming ill.

A direct link between stress and more serious diseases,

however, has been more difficult to establish, Dr. Cohen

said. Recent studies have provided increased support for

the notion that stress contributes to heart disease, and

researchers have tied psychological stress, directly or

indirectly, to diabetes, rheumatoid arthritis,

fibromyalgia, severe depression and other mental disorders.

But the influence of chronic stress on other diseases like

cancer remains controversial. All the same, Dr. Cohen said,

" The evidence that stress puts people at risk for disease

is a lot better than it was 10 years ago. "

The Risks

From an Early Start,

Lifelong Effects

Why do some people

seem more vulnerable to life's pressures than others?

Personality and health habits play a role. And severe

stress in early life appears to cast a long shadow.

Dr. Meaney of McGill University and his colleagues

have found that rat pups intensively licked and groomed by

their mothers were bolder and secreted lower levels of the

stress hormone ACTH in stressful situations than rats

lacking such attention - an equanimity that lasted

throughout their lives. (Cuddled pups, the researchers

found in another study, were also smarter than their

neglected peers.)

In humans, physical and sexual abuse and other traumas in

childhood have been associated with a more pronounced

response to stress later in life. In one study, Dr.

Nemeroff, a psychiatrist at Emory University, and his

colleagues found that women who were physically or sexually

abused as children secreted more of two stress hormones in

response to a mildly stressful situation than women who had

not been abused.

Yet perhaps the best indicator of how people are likely to

be affected by stress is their position in the social

hierarchy. In subordinate male monkeys, for example, the

stress of being servile to their alpha counterparts causes

damage in the hippocampus. And dominant monkeys who are

repeatedly moved from social group to social group, forcing

them to constantly re-establish their position, also

exhibit severe stress and are more likely to develop

atherosclerosis, according to studies by Dr. Jay Kaplan of

Wake Forest University School of Medicine.

Being low in the hierarchy also affects reproduction,

presumably because evolution dictated that in times of

stress, other factors were more pressing than procreation.

In a recent study, Dr. Kaplan found that the constant

low-level harassment by dominant female monkeys shut down

reproductive function in subordinate females and built up

fat deposits in their arteries.

It would be nice to think that humans are less chained to

their social rankings. But alas, researchers have found

this not to be the case. A wealth of studies shows that the

risk for many diseases increases with every step down the

socioeconomic scale, even when factors like smoking and

access to health care are taken into account.

A real estate mogul living in a Park Avenue penthouse has a

better health prognosis than the head of a small company in

an upscale condo a few blocks away. And a renter in a

one-bedroom apartment on the Upper West Side of Manhattan

will be a tier or two lower still in health expectations.

Even people's perceptions of their relative standings in

society affect their disease risk. In one study, led by Dr.

E. Adler, also at the University of California at San

Francisco, women who placed themselves higher on the social

ladder reported better physical health and had lower

resting cortisol levels and less abdominal fat than women

who placed themselves on lower rungs.

No matter what one's circumstances, of course, some stress

in life is inevitable. But illness is not, Dr. McEwen said.

A variety of strategies can help reduce disease risk.

Reaching for a gallon of ice cream to soothe the tension of

a family argument is not one of them, however, nor is

forgoing exercise in favor of curling up on the sofa for an

eight-hour marathon of " Law and Order. "

The best ways to cope, Dr. McEwen said, turn out to be the

time-honored ones: eat sensibly, get plenty of sleep,

exercise regularly, stop at one martini and stay away from

cigarettes. " It's a matter of making choices in your life, "

he said.

http://www.nytimes.com/2002/12/17/health/psychology/17STRE.html?ex=1041321927&ei\

=1&en=6de12b3372c1202c

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