Age-related changes of the hypothalamic-pituitary-adrenal axis: pathophysiological correlates

Abstract

The aim of this review was to examine the evidence for age-related changes of the hypothalamic± pituitary±adrenal (HPA) axis in both physiological and pathological aging, on the basis of the many data in the literature, as well as of our personal findings.A statistically significant circadian rhythmicity of serum cortisol was maintained in elderly subjects, even if with a reduced amplitude of the 24 h fluctuations and a trend to an increase of the serum levels in the evening and at night-time, in comparison with young controls. Furthermore, an age-related impairment of HPA sensitivity to steroid feedback was present in elderly people.The occurrence of senile dementia amplified the changes already present in physiological aging. While the cortisol secretion was generally well maintained in aging, the adrenal production of dehydroepiandrosterone and of its sulfate (DHEAS) exhibited an age-related decline. Therefore, the cortisol/DHEAS molar ratio was significantly higher in elderly subjects and even more in demented ones, than in young controls.Due to the opposite effects of cortisol and DHEAS on the brain and particularly on the hippocampal region, the imbalance between glucocorticoids and androgens occurring in physiological and even more in pathological aging, may have adverse effects on the function of this region, whose key role in learning and memory is well known.

Flattening the Glucocorticoid Rhythm causes Changes in Hippocampal Expression of Messenger RNAs Coding Structural and Functional Proteins: Implications for Aging and Depression

“…In the present study, we used a manipulation that produces glucocorticoid levels that are clamped at the midpoint of the diurnal rhythm and hence are increased at the nadir but decreased at the zenith relative to the normal rhythm. The corticosterone profile generated is very similar to that seen in aged rats (Hauger et al, 1994) and similar to the profile of cortisol levels in aged human subjects (Deuschle et al, 1997a;Ferrari et al, 2001;Van Cauter et al, 1996;Wong et al, 2000). The elevated nadir and flattened rhythm is also consistent with the pattern observed in depressed patients, although in this group the peak of the diurnal rhythm is preserved, or even marginally elevated, resulting in an increase in 24 h cortisol exposure (Deuschle et al, 1997b;Wong et al, 2000).…”

“…However, more subtle changes in glucocorticoid levels are comparatively prevalent, and furthermore often go untreated. Thus in the normal aging process, there is a significant flattening of the normal diurnal rhythm of cortisol secretion (Ferrari et al, 2001;Van Cauter et al, 1996;Deuschle et al, 1997a). In addition, several common psychiatric disorders including affective disorders, cortisol secretion is moderately increased and there is a marked flattening of the diurnal rhythm (Deuschle et al, 1997b;Ferrari et al, 2001).…”

Serum factors in older individuals change cellular clock properties

“…Even if the peripheral cells of elderly subjects do not differ from younger subjects in their chronobiological properties, it is well documented that the milieu in which these cells are found undergoes dramatic changes as individuals age (7,31), and peripheral organs certainly show altered function with aging (7,13,14,17,32), If cellular circadian properties per se do not change with aging, we reasoned that age-related circadian alterations might be provoked by a circulating factor. To test this possibility, YF2 YF3 YF4 YF5 YF6 YF7 YM1 YM2 YM3 YM4 YM5 YM6 YM7 YM8 YM9 YM10 YM11 OF1 OF2 OF3 OF4 OF5 OF6 OF7 OM1 OM2 OM3 OM4 OM5 OM6 OM7 OM8 OM9 OM10 OM11 23.…”

“…Older individuals have an earlier phase of everyday activity compared with the young (4). Not only is the consolidation of sleep and wake dramatically reduced (5,6), but overall circadian amplitude of hormones and body temperature are lower (7,8), and many agingassociated sleep-wake pathologies have been reported (9)(10)(11). As a result, one in five healthy older individuals reports taking sleep medications regularly (9).…”

“…In cases of pathological aging, chronobiological disturbance is even more acute: Huntington disease, Parkinson disease, and Alzheimer's disease are all associated with profound alterations in sleeping patterns (10)(11)(12). These effects of aging on circadian rhythms-diminished circadian amplitude, earlier phase, shorter circadian period, and desynchronization of rhythms in peripheral organs-have been observed widely in several species of mammals (7,13,14). Paradoxically, however, even though the behavioral phase is earlier in aged humans, multiple studies conclude that the free-running period remains unchanged (15)(16)(17)(18).…”