The HPA Axis under Stress and Aging: Individual Vulnerability is Associated with Behavioral Patterns and Exposure Time.

With aging, incidence of severe stress-related diseases increases. However, mechanisms, underlying individual vulnerability to stress and age-related diseases are not clear. The goal of this review is to analyze finding from the recent literature on age-related characteristics of the hypothalamic-pituitary-adrenal (HPA) axis associated with stress reactivity in animals that show behavioral signs of anxiety and depression under mild stress, and in human patients with anxiety disorders and depression with emphasis on the impact of the circadian rhythm and the negative feedback mechanisms involved in the stress response. One can conclude that HPA axis reaction to psycho-emotional stress, at least acute stress, increases in the aged individuals with anxiety and depression behavior. Elevated stress reactivity is associated with disruption of the circadian rhythm and the mineralocorticoid receptor-mediated glucocorticoid negative feedback. The disordered function of the HPA axis in individuals with anxiety and depression behavior can contribute to aging-related pathology.

Age-related differences in stress responsiveness of the hypothalamic-pituitary-adrenal axis of nonhuman primates with various types of adaptive behavior.

Aging is characterized by disturbances in the functioning of the hypothalamic-pituitary-adrenal (HPA) axis, associated with disturbances in the adaptation processes and increase of the probability of the onset of post-stress syndrome. However, the individual features of age-related disorders stress reactivity of HPA axis have not been studied. The purpose was to study individual characteristics of the HPA axis responsiveness to acute psycho-emotional stress exposure (restraint, ASE) at different age periods on the model of the young adult and old physically healthy female rhesus monkeys that differ in their behavioral responses to stress, i.e., with depression-like and anxiety-like behavior (DAB) on the one hand and healthy standard (control) adaptive behavior (SB) on the other hand. No significant intergroup differences were observed in HPA axis responses to ASE in young animals. During aging the monkeys with SB showed reduced ACTH response to the ASE, whereas the monkeys with DAB demonstrated its increase. The old animals with DAB in response to ASE demonstrated the most pronounced HPA axis disorders, such as the highest levels of corticotrophin (ACTH), the lowest levels of dehydroepiandrosterone sulfate (DHEAS), reduced cortisol (F) levels and the highest values of the F/DHEAS molar ratio. The ratio F/DHEAS positively correlates with the malondialdehyde concentration in erythrocytes that is considered as the biomarker of oxidative stress. Thus, these data allow us to consider the old monkeys with DAB as individuals with higher vulnerability to the adverse effects of ASE. In addition, depression-like and anxiety-like behavior of aged primates under mild/moderate stress along with reduced DHEAS plasma concentration and increased values of F/DHEAS ratio can be used to identify individuals with increased vulnerability to ASE and accelerated aging.

Correlation between activity of antioxidant enzymes and circadian rhythms of corticosteroids in Macaca mulatta monkeys of different age.

Young rhesus monkey females (Macaca mulatta) demonstrate the well-defined circadian rhythm in activity of erythrocyte SOD with maximum at 10.00 h and minimum at 22.00 h. However, neither GSH-Px nor GR demonstrated any significant circadian changes, contrastingly to SOD. The diurnal changes in the SOD activity tightly correlate with the diurnal changes in the levels of cortisol and DHEAS in the animals' blood plasma. With aging, these circadian rhythms of SOD, cortisol and DHEAS are smoothed out although the correlation between the diurnal changes in cortisol and SOD still maintains even for old animals. These results suggest that corticosteroids play an essential role in regulation of the SOD activity and that the reliability of the hormonal regulation decreases with aging.

Effects of aging on hypothalamic-pituitary-adrenal system function in non-human primates.

The study was aimed at characterizing the changes in hypothalamic-pituitary-adrenal (HPA) axis function during aging in monkey models (Papio hamadryas and Macaca mulatta). It has been established by specific radioimmunoassay and enzyme immunoassay that basal plasma levels of adrenal androgenes (dehydroepiandrosterone-DHEA, dehydroepiandrosterone sulfate-DHEAS) and the early precursors of steroid hormones (pregnenolone and 17-hydroxypregnenolone) progressively decrease with age in baboons and macaques, while cortisol and 11-desoxycortisol concentrations do not change. The old female rhesus monkeys exhibited a higher cortisol and corticosterone response, but a lower DHEAS response to corticotropin-releasing hormone (CRH) administration then the young monkeys. The aged rhesus monkeys also exhibited a decrease of the adrenal cortex resiliency, that was manifested in the deceleration of the decrease of cortisol concentrations after the peak values had been reached in response to ACTH 1-39 administration. At the same time the ACTH 1-24 depot test revealed no age-related changes in the maximum capacity of monkey adrenals to synthesize and secrete cortisol. The aged monkeys also developed less sensitivity of the HPA axis to dexametasone suppression test. The age-related hormonal changes may play an important role in the age-related involutive processes and in the disorders of the adaptive ability of old organisms.

Stress responsiveness of the hypothalamic-pituitary-adrenal axis: age-related features of the vasopressinergic regulation.

The hypothalamic-pituitary-adrenal (HPA) axis plays a key role in adaptation to environmental stresses. Parvicellular neurons of the hypothalamic paraventricular nucleus secrete corticotrophin releasing hormone (CRH) and arginine vasopressin (AVP) into pituitary portal system; CRH and AVP stimulate adrenocorticotropic hormone (ACTH) release through specific G-protein-coupled membrane receptors on pituitary corticotrophs, CRHR1 for CRH and V1b for AVP; the adrenal gland cortex secretes glucocorticoids in response to ACTH. The glucocorticoids activate specific receptors in brain and peripheral tissues thereby triggering the necessary metabolic, immune, neuromodulatory, and behavioral changes to resist stress. While importance of CRH, as a key hypothalamic factor of HPA axis regulation in basal and stress conditions in most species, is generally recognized, role of AVP remains to be clarified. This review focuses on the role of AVP in the regulation of stress responsiveness of the HPA axis with emphasis on the effects of aging on vasopressinergic regulation of HPA axis stress responsiveness. Under most of the known stressors, AVP is necessary for acute ACTH secretion but in a context-specific manner. The current data on the AVP role in regulation of HPA responsiveness to chronic stress in adulthood are rather contradictory. The importance of the vasopressinergic regulation of the HPA stress responsiveness is greatest during fetal development, in neonatal period, and in the lactating adult. Aging associated with increased variability in several parameters of HPA function including basal state, responsiveness to stressors, and special testing. Reports on the possible role of the AVP/V1b receptor system in the increase of HPA axis hyperactivity with aging are contradictory and requires further research. Many contradictory results may be due to age and species differences in the HPA function of rodents and primates.

Age-related changes in the reliability of antioxidant enzyme defense in monkeys with different types of adaptive behavior.

We have investigated age-related changes in the reliability of glutathione-related antioxidant enzyme defense in monkeys that differ in adaptive behavior. Activities of gluthatione reductase (GR), glutathione peroxidase (GSH-Px), and gluthatione-S-transferase (GST) and also lipid peroxidation products (TBARS) under basal conditions and under acute psycho-emotional stress were evaluated in erythrocytes of young (6-8 years) and old (20-27 years) female rhesus monkeys with depression-like and standard (control) behavior. We have found that young animals with depression-like behavior, in comparison with young monkeys of standard behavior, demonstrated higher activity of GR in basal conditions and no significant changes in response to acute immobilization stress. With aging the activity of GR increased in monkeys with standard behavior in basal conditions but retained the ability to increase under acute stress. At the same time during aging in monkeys with depression-like behavior GR activity did not undergo significant changes in basal conditions and did not change in response to acute stress. Moreover, old animals with depression-like behavior demonstrated reduced activity of GSH-Px. More pronounced disturbances in GR and GSH-Px activities in animals with depression-like behavior evidence a more marked decrease in the reliability of antioxidant enzyme defense of cells and lead to activation of lipid peroxidation that may be considered as an important factor of aging. Thus, age-related dysfunctions of the antioxidant enzyme system correlate with the type of adaptive behavior characteristic of animals.

Aging of the hypothalamic-pituitary-adrenal axis in nonhuman primates with depression-like and aggressive behavior.

We have investigated aging of the hypothalamic-pituitary-adrenal (HPA) axis in female rhesus monkeys that differ in adaptive behavior. Plasma cortisol (F) and dehydroepiandrosterone sulfate (DHEA-S) concentrations under basal conditions and under acute psycho-emotional stress were evaluated in blood plasma of young (6-8 years) and old (20-27 years) female rhesus monkeys with various types of adaptive behavior (aggressive, depression-like, and average). We have found that the age-related changes in the HPA axis of monkeys with depression-like behavior were accompanied by the maximal absolute and relative hypercortisolemia under both basal conditions and stress. Moreover, young aggressive monkeys, in comparison with young monkeys of other behavior groups, demonstrated the highest plasma levels of DHEA-S and the lowest molar ratios between F and DHEA-S. Thus, age-related dysfunctions of the HPA axis are associated with adaptive behavior of animals.

Stress, aging and reliability of antioxidant enzyme defense.

Clinical and experimental data point to existence of disturbances of adaptive ability of aged organism to extreme impacts. However mechanisms of these disturbances are not clear yet. The purpose of the investigation was to study age-related changes in reaction of erythrocyte antioxidant enzyme system in response to acute psycho-emotional stress and a possible role of these changes in age-related alterations of oxygen blood transport in nonhuman primates. Ten young (6-8 years) and ten old (20-26 years) healthy female rhesus monkeys were subjected to acute moderate psycho-emotional stress (two hours squeeze cage restraint) at 1500h. Plasma cortisol, lipid peroxidation products (TBARS) and activities of superoxide dismutase (SOD), glutathione peroxidase, gluthatione reductase (GR), and gluthatione-S-transferase in erythrocytes were measured before stress and at 30, 60, 120, 240 min and 24 hours after beginning of the stress. We have found for the first time that SOD activity decreased in response to the stress in young monkeys while it increased in the half of old monkeys. Young animals also demonstrated essentially higher increase in GR activity and plasma cortisol level in response to the restraint in comparison with old monkeys. Level of TBARS did not practically change in response to the stress in young animals and significantly increased in old monkeys. The study demonstrated that the age-related alterations in SOD and GR stress responsiveness lead to activation of peroxide oxidation of lipids that may be considered as an important factor of aging damage of erythrocyte functioning and reliability of oxygen transport to tissues under stress conditions.

Circadian and age-related changes in stress responsiveness of the adrenal cortex and erythrocyte antioxidant enzymes in female rhesus monkeys.

BACKGROUND: The objective of this study was to evaluate the role of the adrenal cortex in the regulation of antioxidant enzyme defense and to characterize this regulation in different age periods. METHODS: Five young and five old female rhesus monkeys were subjected to 2 hours squeeze cage restraint stress at 0900 or 1500 hours. Plasma levels of corticosteroids and activities of erythrocyte antioxidant enzymes were measured before the stress and 30, 60, 120, 240 minutes after beginning of the stress. RESULTS: Young monkeys showed a circadian rhythm in stress responsiveness as measured by corticosteroids and glutathione reductase. The rhythm was attenuated in old animals. Age-related changes in the overall level of response to the afternoon stress were also seen in the corticosteroid and glutathione reductase measures. CONCLUSIONS: The study demonstrated that corticosteroids play an essential role in the regulation of antioxidant enzyme defense in stress conditions and that the reliability of their regulation decreases with age.