Many of the diseases we associate with ageing - such as heart disease, cancer, dementia and stroke - may be the result of lifelong, poorly managed stress.
A body under stress is a chemically altered body. It is a body awash in hormones and other substances that are normally kept under tight control. In the right proportions, hormones such as catecholamines - including dopamine, epinephrine (adrenaline) and norepinephrine (noradrenaline) - glucocortoids such as cortisol and androgens such as dehydroepiandrosterone (DHEA) keep our bodies healthy. But too much or too little of these substances and they become a form of slow poison, leading to a staggering list of stress-related disorders.
The list now includes fatigue, indigestion, infections, irritability, diarrhoea, eczema, headaches, constipation, psoriasis, muscle tension, peptic ulcer, allergies, neck and back pain, irritable bowel, asthma, atherosclerosis, loss of appetite, nutritional deficiencies, high blood pressure, anorexia nervosa, premenstrual symptoms, diabetes, weight changes, sexual problems, arthritis, insomnia, psychological problems, cancer and depression. Indeed, no part of our lives remains untouched by stress.
The key to stress survival is allostasis - the body's ability to achieve harmony through change (N Engl J Med, 1998; 338: 171-8). Through allostasis, two adaptive pathways - the hypothalamic-pituitary-adrenal (HPA) axis and the sympatho-adrenal-medullary (SAM) axis which controls the sympathetic nervous system - are initiated. Activation of these pathways leads to many neuroendocrinological changes, such as raised hormones and proteins such as cortisol, epinephrine, norepinephrine, calcitonin, gastrin and insulin, which can result in common fight-or-flight responses such as elevations in blood pressure, heart and sweat rate, coagulation time and blood-glucose levels.
Of these, cortisol and DHEA have been the most widely studied. During episodes of acute stress, hormones such as cortisol at first protect us by activating the body's defences through a complex chain of biochemical events. But, when these same protective hormones are produced repeatedly or in excess, they create a gradual and steady cascade of harmful physiological changes.
As levels of cortisol rise in response to chronic stress, levels of another hormone - DHEA - drop. The result can be hypothyroidism, heart disease, prostate and breast cancer, menstrual irregularities, osteoporosis and autoimmune disorders such as systemic lupus erythmatosus (SLE) and rheumatoid arthritis (Clin Exp Immunol, 1995; 99: 251-5; Clin Exp Rheumatol, 1992; 10: 25-30).
Most of us think of stress as being emotional in origin. Indeed, most major assessments of life stress take into account events such as bereavement, marriage and unemployment. But the body does not differentiate between these and other kinds of stress, such as physical, chemical, nutritional, traumatic and even psychospiritual. In addition, it is not just major stressors that cause problems. There is evidence that high numbers of small daily hassles can also take their toll (Psychosom Med, 1994; 56: 216-24).
Whatever the source and intensity, the body responds when under attack by releasing a flood of stress hormones to help it maintain balance. The problem is that a body that is constantly adjusting itself to stressors is subject to a great deal of wear and tear. In all this overactivity, the allostatic systems become worn out, leading to an inability to either adapt or shut off (and thus reduce levels of circulating stress hormones) after the resolution of a stressful event (Endocrinol Rev, 1994; 15: 233-60). When this happens, the usual recommendations, such as relaxation and exercise, may no longer be enough to counteract the effects of stress.
We now know that a body awash in stress hormones for years at a time is most likely to develop a range of diseases, such as cardiovascular disease, and loss of cognitive and physical functioning, all of which modern physicians consider common with advancing age.
A lifetime of job stress (high psychological demands and a lack of control) can accelerate the progression of atherosclerosis and heart failure (BMJ, 1997; 314: 553-8; Arterioscler Thromb Vasc Biol, 1996; 16: 363-7; BMJ, 1985; 291: 1312-4). Caring for a spouse or relative who is ill, say, with Alzheimer's can also lead to a greater risk of coronary heart disease (Psychosom Med, 2002; 64: 418-35).
Higher cortisol levels have been recorded in patients at the onset of a myocardial infarction (Exp Clin Endocrinol, 1992; 99: 68-70; Clin Endocrinol, 1994; 40: 499-504). Stress can also raise blood pressure (Hypertension, 2002; 139: 184-8), create harmful free radicals and raise levels of homocysteine, which damages cell linings and arterial walls (Life Sci, 2000; 66: 2267-75; Life Sci, 1999; 64: 2359-65).
A nine-year study in Japan of 73,000 people showed that women who reported high mental stress were more than twice as likely to have a fatal stroke than those reporting low stress, and about two times as likely to have a deadly heart attack. Men who reported high mental stress were about 1.5 times more likely to die from a heart attack, but did not show significantly increased deaths overall due to stroke (Circulation, 2002; 106: 1229-36).
Although the women who reported high stress were more sedentary, more likely to have a history of hypertension or diabetes, smoked more and were more likely to work fulltime, the researchers noted that, even after adjusting for these factors, the association between stress and heart attacks in both women and men, and between stress and strokes in women, remained.
Stress can also lead to poor eating habits, poor glucose control and obesity (Prev Med, 2002; 34: 29-39; Psychosom Med, 1996; 58: 489-99) - cornerstones of many diseases later in life.
Indeed, a theory known as the 'stress cascade' suggests an interconnection between stress, diabetes, obesity, hypertension and altered lipoprotein metabolism (Clin Sci, 1989; 77: 453-61). The stress cascade results in the release of increasingly larger amounts of catecholamines and corticosteroids which, in turn, affect insulin regulation, glucose metabolism and fat storage. Sustained cortisol output due to stress increases insulin insensitivity, which tends to lead to a decreased tissue-glucose uptake. When this happens, insulin secretion increases to counteract the increased insulin insensitivity.
The long-term elevations of cortisol and the secondary raised insulin levels also increase fatty acid, glycogen and lipoprotein lipase synthesis in fat tissues, creating ideal conditions for the development of high cholesterol and triglyceride levels in the blood - risk factors for atherosclerosis.
At the other end of the scale, Norwegian researchers have found that stress is a more influential factor in the development of Graves' disease (an overactive thyroid) than genetics. In a study of 219 persons newly diagnosed with Graves' disease and matched with 372 controls, those who were under stress had 6.3 times the risk of developing the disease compared with 3.6 times for those with a family history of the disease (Lancet, 1991; 338: 1475-9).
Immunity and cancer
The ability of stress to alter immune function and to precipitate and aggravate infectious diseases has long been recognised (J Fla Med Assoc, 1993; 80: 409-11; Arch Psych Nurs, 1994; 8: 221-7). Today, suppressed immunity is recognised as a major problem associated with chronic exposure to stress hormones (Psychosom Med, 2002; 64: 15-28; Psychosom Med, 1992; 54: 680-5; Psychol Inquiry, 1991; 2: 249-51; Behav Immunol, 1988; 2, 67-78; Soc Neurosci, 1996; 22: 1350; N Engl J Med, 1991; 325: 606-12; JAMA, 1999; 281: 2268-70).
The effects of this impaired immune function can be seen in studies showing poor wound-healing in stressed individuals (Arch Gen Psychiatry, 1999; 56: 450-6; Lancet, 1995; 346: 1194-6; J Periodontol, 1999; 70: 786-92; Am Psychol, 1998; 53: 1209-18) as well as an increased susceptibility to colds and flu (N Engl J Med, 1991; 325: 606-12; Psychosom Med, 1999; 61: 175-80; J Psychosom Res, 1997; 43: 271-8; Health Psychol, 1998; 17: 214-23).
We are only just beginning to understand the ways in which stress can alter immunity. Initially, the surge of brain and adrenal hormones that accompanies stress causes an increase in circulating white blood cells. But when cortisol levels remain high, white blood cell numbers decline. The immunosuppressive effect of cortisol has also been found to contribute to reductions in lymphocyte numbers and their effectiveness (J Consult Clin Psychol, 1992; 60: 569-75; Psychol Bull, 1990; 103: 363-82). Cortisol also inhibits the production of cytokines (compounds involved in the inflammatory response) which, in turn, can be detrimental to the body's response to immune challenges (Psychosom Med, 1999; 61: 175-80).
Poor immunity has been documented in studies of caregivers of those with Alzheimer's disease (Ann Behav Med, 1987; 9: 16-20). Indeed, along with caring for family members with progressive dementia, other chronic stressors such as poor marital relationships and divorce have been associated with eventual suppression, rather than adaptation, of the immune response (Psychosom Med, 1996; 58: 264-72; Psychosom Med, 1987; 49: 13-34; Psychosom Med, 1988; 50: 213-29; Psychol Inquiry, 1991; 2: 249-51).
There is also an evolving belief that poor immunity as a result of chronic stress may also contribute to the development of cancer. Retrospective studies have found an association between acute loss, bereavement, depression and subsequent development of several types of cancer, including colorectal and prostate cancers (Psychosomatics, 1981; 21: 975-80; Ann NY Acad Sci, 1966; 125: 820-6; Ann NY Acad Sci, 1966; 125: 780-93; Health Psychol, 1999; 18: 482-6).
But it has been the development and progression of breast cancer in relation to life stress that has undergone the most study (BMJ, 1996; 312: 845; Cancer, 1996; 77: 1015-6; J Behav Med, 1978; 1: 133; Science, 1979; 205: 513-5). Women with advanced breast cancer have been found to have high daytime levels of cortisol whereas, in general, cortisol levels are high first thing in the morning, drop during the day and are at their lowest around midnight. Such women die, on average, a year sooner from their condition than those with normal cortisol levels (J Natl Cancer Inst, 2000; 92: 994-1000; Lancet, 1989; ii: 888-91).
Natural killer (NK)-cell activity is important in the prevention of breast cancer metastasis (J Clin Oncol, 1987; 5: 348-53), and there is evidence that women with breast cancer tend to have significantly reduced NK destruction of tumour cells compared with women who have benign breast disease or healthy breasts (Br J Cancer, 1982; 46: 611-6; Health Psychol, 1985; 4: 99-113). In some women, chronic stress can suppress NK activity.
Other evidence suggests that breast cancer patients who have experienced a high number of severe, adverse life events during their illness appear to have shorter remission times than those patients who report fewer or less severe, adverse life events during their illness (BMJ, 1989; 298: 291-3).
And while conventional medicine still disputes the link, women themselves know instinctively that stress is influential. In a study of nearly 400 breast cancer survivors who had been disease-free for nine years, 42 per cent said they believed that stress was one of the main causes of their breast cancer (Psycho-Oncology, 2001; 10: 179-83). This idea has been confirmed by scientists who have found that women under stress from bereavement, job loss or divorce have almost a 12-fold increased risk of developing breast cancer within five years (BMJ, 1995; 311: 1527-30).
Stress, memory and mood
Stress doesn't just poison the physical body; it also has a profound effect on our mind and mood. The same HPA activity that causes physical disorders in some can cause mental and emotional disorders in others.
Long-term stress can also affect memory by destroying neurons in the hippocampus, the area of the brain that contributes to visual memory and context (J Neurosci, 1989; 9: 1705-11; Sapolsky RM, Stress: The Aging Brain and the Mechanisms of Neuron Death, Cambridge, MA: MIT Press, 1992). Poor dietary habits associated with stress may also contribute to a range of psychological problems such as depression and anxiety (J Am Diet Assoc, 2002; 102: 699-703).
Stress can also contribute to disease like Alzheimer's. Hormones such as cortisol - increased during stress - block the ability of glucose to gain entry into brain cells. Unlike other tissues, glucose is the only source of energy for the brain, and some structures, like the hippocampus - that part of the brain that helps to maintain learning and memory skills, particularly the kind of short-term memory that allows you to remember the list of things you went to buy at the supermarket - are affected more by this deprivation than others.
In addition, there is evidence to show that women with Alzheimer's tend to have low levels of DHEA in relation to cortisol (Psychopharmacology [Berl], 1993; 111: 23-6).
Worse, a daily dose of stress hormones can cause the hippocampus to shrink. There is evidence, for instance, that the hippocampus of individuals suffering from post-traumatic stress disorder (PTSD) as a result of serving in the Vietnam war or because of childhood abuse is significantly smaller than normal (Biol Psychiatry, 1999; 45: 797-805; Arch Gen Psychiatry, 2000; 57: 925-35).
Depressed individuals often have significantly higher morning and midnight salivary cortisol levels (Am J Psychiatry, 1991; 148: 505-8; Biol Psychiatry, 1987; 18: 1-4; Eur Arch Psychiatr Neurol Sci, 1987; 237: 36-45) and disrupted circadian rhythms (Psychiatr Res, 1990; 37: 237-44; Horm Res, 1982; 16: 357-64; Arch Gen Psychiatry, 1973; 28: 19-24). At the extreme end of the scale, about 60.6 per cent of patients with chronic schizophrenia also show abnormal cortisol levels (Neuropsychobiology, 1992; 25: 1-7).
While depressed patients frequently complain of difficulties with concentration and memory, the problems associated with higher cortisol levels don't begin and end with memory. In the same way that higher cortisol levels in athletes who have exercise-related amenorrhoea (lack of menstrual periods) correlate with significantly low bone mineral density (Ann Intern Med, 1988; 108: 530-4), women with a history of depressive illness - characterised by chronic, moderately raised levels of serum cortisol - are also more likely to have decreased bone mineral density (N Engl J Med, 1996; 335: 1176-81). These findings mirror those in women who have had their ovaries removed - an operation that can lead to osteoporosis and poor calcium absorption - again as a result of increased cortisol levels (Lancet, 1979; ii: 597).
The overwhelming evidence is that many of the diseases we associate with ageing may, in part, be the result of lifelong and poorly managed stress. Indeed, there is now ample evidence that stress has measurable effects on ageing and longevity, and it is those with the lowest levels of stress who, in the end, will experience the least cognitive and physical decline with age (J Clin Endocrinol Metab, 1997; 82: 2458-65).
The inferences from this are profound. While our doctors - who have long disputed the influence of stress on health - play catch-up with the growing evidence of the deleterious effects of stress, we may all be dying earlier and from diseases we need not have had in the first place. Instead of popping pills, lessons in stress survival may eventually be the thing that saves us all.