Studies in humans

The brain functions involved are those responsible for primitive survival reactions. Studies in non-human primates have shown essentially the same reaction pattern as in rodents (Uno et al 1989). Therefore a similar chain of reaction would also be expected in humans. The situation is, however, more difficult to evaluate in humans, who typically experience a wide variety of external challenges during a long life, with presumably varying vulnerability.

Several difficulties are apparent with the available human studies. These include variables such as the selection of study groups, whether the study group is healthy or not, sample size, the extent of the age differences in the groups, and perhaps the most important problem, the techniques utilized for assaying HPA axis function. This latter problem is particularly important in human studies because of the exquisite sensitivity of the reactions to be followed, as will be illustrated.

Furthermore, fully controlled experiments are difficult to perform in this area of research. These problems make many studies of limited value, which has been taken into account in the following evaluation.

Although the results are not totally consistent, they indicate that the basal, non-stimulated HPA axis and circadian rhythm are not disturbed in old subjects (Seeman & Robbins 1994). Stimulation by adrenocorticotropic hormone (ACTH) is apparently also followed by a normal initial response of cortisol while there might be a delayed return to normal values (Blichert-Toft 1975, West et al 1961). In general, studies with stimulation by corticotrophin-releasing hormone are difficult to evaluate, largely because of small sample sizes. However, one such study also suggests that the return to baseline cortisol values after such stimulations is prolonged in older individuals (Pavlov et al 1986).

Tests of the function of the feedback mechanism in humans usually involve the administration of dexamethasone and followed by the inhibition of cortisol secretion. These results are of particular importance in view of the evidence for a deficient feedback regulation in old animals. With the conventional dose of dexamethasone (1 mg) results have been largely normal, when calculated as inhibition below a certain given 'normal' level (Green & Friedman 1968), while old subjects seem to have higher mean absolute values after suppression (Tourigny-Rivard et al 1981). When inhibition with lower doses (0.5 mg) is tested to improve sensitivity, there is better evidence for a blunted inhibition in older subjects (Oxenkrug et al 1983, Branconnier et al 1984).

Most of the studies referred to have only measured the concentrations of circulating hormones, which are a result of secretion and clearance. One study indicates that there is no difference in clearance of cortisol (Barton et al 1993). The cortisol levels after various challenges are most likely a result of secretion without much influence of removal rates, although the latter cannot be stated with certainty.

Several studies have been performed in subjects with various diseases that might be suspected to be consequences of HPA axis activation over prolonged periods. Conditions with increased cortisol secretion due to tumours (such as Cushing's syndrome) or with elevated exposure to glucocorticoids due to therapeutic interventions are followed by insulin resistance, abdominal obesity, hypertension, dyslipidaemia, osteoporosis, cognitive impairments and immune deficiencies (Seeman & Robbins 1994). These are consequences of elevated glucocorticoid exposure where the mechanisms are essentially known.

Conditions with similar phylogenetic expression to these overexposures to glucocorticoids are hypertension, cardiovascular disease and type 2 diabetes mellitus. These conditions are suggested to have impairments of HPA axis regulation (Seeman & Robbins 1994). This might be a consequence of the diseased state, but it is possible that these diseases are in fact at least partly consequences of primary dysregulation of the HPA axis.

In an attempt to summarize the human data, there is no conclusive evidence that ageing per se is associated with a faulty regulation of the HPA axis, although this must be considered impossible to study in a meaningful way because it requires all external influences to be absent. There is, however, suggestive evidence that in the ageing person there is often a diminished rate of return of cortisol secretion to basal values after challenge, which may be due to an inefficient feedback regulation. This would then agree with the better-controlled animal data on the input of ageing. It is impossible, however, to judge whether this is a consequence of the ageing process or due to repeated exposure to stressful events during a long life. Normal ageing is unavoidably associated with exposure to the wear and tear of daily life. There are clearly individual differences in the sensitivity and perception of such challenges, and these differences most likely have a genetic basis. Increased frequency of periods of stress during a lifetime would be expected to increase the vulnerability to diseases via effects on metabolic and other processes, as will be discussed in a following section.

Another approach to this problem is the following. If it is supposed that the HPA axis and its associated cascade of events are affected by ageing, then it is interesting to know what characterizes subjects who have been able to maintain a normal HPA axis function into an advanced age. The function of the HPA axis has been followed longitudinally for a long period in a group of healthy subjects. Those without signs of deterioration of this function were characterized by good memory and selective attention (Lupien et al 1994) as well as preserved hippocampal structure (Lupien et al 1998). Whether these differences are genetically determined and localized to the HPA axis regulation itself, or to a resistance to environmental 'stressors', or both, is not known.

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