Feature: Pressure points

7 November 2006. By Chrissie Giles

Helpful in the short term, but detrimental in the long term, stress has profound effects on the body and mind.

For material physicists, it's force per unit area; for a cell, it's oxygen deprivation; and for a lab rat, it's a new cage full of unknown newcomers or the odour of a predator. For most of us, it's missing the bus, finding that someone's used all the milk, or having too much to do. Stress - it's a term we all use, but what does it actually mean?

"I have only spent about 50 years trying to define stress," says Seymour Levine, Professor of Psychiatry at the University of California, Davis, USA. So if world experts have problems defining it, what are the rest of us meant to do?

"Quite often when people say 'I am stressed', they mean that they are experiencing certain physiological manifestations: the rapid heartbeat, sweating, tingling and shaking," says Jonathan Seckl, Professor of Molecular Medicine at the University of Edinburgh. So lay interpretations of stress do incorporate some sense of what is happening biologically.

Hormonal responses, the key 'read-out' of how stressed the body is, come in two main categories. First is the classic 'fight-or-flight' response, mediated by adrenaline and noradrenaline, which is an immediate response, ready to turn on muscles, tone up blood vessels and activate certain parts of the brain. Second is the glucocorticoid response, which causes blood sugar and fat levels to increase, providing fuel for muscles and brain, and triggers a rise in blood pressure. Nonessential processes, including memory, digestion and inflammation, are slowed.

Certain diseases affect the stress responses. A stark illustration of this is Addison's disease, which is characterised by an inability to produce stress hormones called glucocorticoids (such as cortisol; also known as hydrocortisone). "With Addison's, you're stressed, break a leg or get a nasty infection, and you may die," says Professor Seckl, who is funded by the Wellcome Trust.

At the hub of the stress response is the brain, processing different stressful inputs and coordinating the appropriate response. But what does stress do to us psychologically?

"When we're subjected to something very stressful, our attention narrows to focus on specific themes," says David Clark, Professor of Psychology at the Institute of Psychiatry in London. "Just like when our ancestors heard a rustle in the bushes, a stress stimulus causes you to stop doing what you're doing and focus attention on the potential source of the stimulus."

This perceptual narrowing can help in situations where you need to focus on finding an exit or escape route, for example. But when this stress response is triggered inappropriately (as in anxiety disorders), it can become problematic.

"When an agoraphobic is in a shop, their level of physiological arousal is inappropriate for the real danger there, and their heart races as a result," says Professor Clark. The physical response itself can then become a source of perceived danger. "This kind of response may be appropriate if you meet a sabre-toothed tiger, but generally isn't when you're in Marks and Spencer."

Early life events

We all respond to stress differently. Mental and/or physical illness can affect stress responses, and there is a genetic component in the magnitude of response launched to a particular stressor. But, aside from passing on their genes, our parents also influence how we respond to stressful events in a much subtler way too. So-called 'early life events' (those that occur shortly before or after birth) can affect how we respond to events through our entire lives. Called 'developmental programming' and underpinned by the molecular processes of epigenetics, this is one the hottest areas of stress research at the moment.

"Broadly, what we call a disadvantageous intrauterine environment, such as having a mother who is stressed or malnourished during pregnancy, can hardwire the magnitude of hormonal responses to stress through a person's lifespan," says Professor Seckl.

Some of these effects occur at the basic molecular level, through a process called DNA methylation. Put simply, the regulatory regions of the genes for hormone receptors in the offspring are opened or closed up by DNA methylation, itself controlled by the stress the mother perceives.

"It's a way to adapt your metabolism so that you're set up optimally for your predicted environment. You then have the best chance of getting to adulthood, reproducing and getting on with the next generation," says Professor Seckl.

"The gene is not a fixed event," says Professor Levine, "but is affected by events in the early environment."

The emergence of epigenetics in the stress field owes much to animal studies, including the finding that exposure to stress hormones in fetal rats had effects on glucose and insulin levels in the next two generations. These findings were mirrored in human studies: in a stable Swedish population, an individual's risk of diabetes was found to be, in part, determined by their grandfather's level of nutrition as a child.

Progress in stress research has also come from examining the effects of disasters, accidents and other negative events on people. "Ethically, laboratory studies on stress in humans are brief exposures to non-invasive events," says Professor Levine. "Thus you have to study humans naturalistically when highly stressful conditions prevail, such as 9/11, and under different sets of stressful circumstances."

Professor Seckl and colleagues in New York studied pregnant women who were involved directly in the 9/11 tragedy. The babies of the women who suffered post-traumatic stress disorder (PTSD) showed altered stress responses at age one, compared with those of women without PTSD. Interestingly though, this 'transmission' of a stressor to children was only seen in women who were in the final third of pregnancy during the tragedy.

Long-term trouble

So, while the ability to respond to stress is vital for survival, chronic elevation of the stress response can have serious consequences.

Sir Michael Marmot, Professor of Epidemiology and Public Health, University College London, researches the health consequences of stress in the workplace. In the 'Whitehall II' study, his team looked at stress at work in British civil servants. "We found a remarkable social gradient of disease. Those with a lower social status had a higher incidence of disease and higher mortality," he says.

The team found that about a third of this social gradient was caused by the usual culprits (such as smoking, cholesterol levels and blood pressure). So they also considered work-related factors and found that, independent of a person's position at work, low levels of control over their job predicted the development of cardiovascular, musculoskeletal and mental disorders. Work by the group published in early 2006 showed that people exposed to chronic stress in the workplace were over twice as likely to develop the metabolic syndrome as unstressed colleagues.

Surprisingly similar findings have come from the work of Robert Sapolsky at Stanford University in California, USA. He has spent parts of the last 30 years studying troops of wild baboons in a national park in East Africa, and sees marked relationships between a baboon's social rank and bodily health, in strikingly similar ways to those of the Whitehall study. "One drawback of the human studies is the effort that has to be expended separating the effects of social status per se from the lifestyle risk factors that are often associated with social status. Baboons bypass this: socially subordinate baboons don't smoke, don't drink to excess, and don't lie on questionnaires. So if you see a social status/health relationship, you know that it is a pretty direct one."

"Chronic stress marks the switch of short-term benefit to long-term harm," says Professor Seckl. "The rise of blood glucose levels becomes diabetes, the rise of blood pressure becomes hypertension. Chronic stress is a challenge we're not set up well to meet."

But do we want to lead a completely stress-free life? Hans Selye, the pioneer in stress research, classified stress as distress or positive stress, and Professor Levine argues that life needs a little stress. "Life without stress would be terribly dull," he says. "The stress systems are there for very good reasons, and the well-adjusted individual responds to stress appropriately by a variety of mechanisms. I doubt that many of my activities - skiing, tennis and poker - would be possible, let alone enjoyable, if the stress systems were not activated."

Chrissie Giles is a writer at the Wellcome trust.

Feature: Pressure points

Early life events

Long-term trouble

Further reading