The Heavy Cost of Chronic Stress

December 17, 2002

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

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. Ronald 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. Robert M. Sapolsky, a professor of neurology at

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.
Joseph 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. Michael 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. Charles
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.
Nancy 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. 17STRE.html?ex=1041152023&ei=1&en=3c11622be1474a49


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