Individual Features of the Hypothalamic-Pituitary-Thyroid Axis Functioning during Aging in Non-Human Primates.

Individual features of age-related changes in the function of the neuroendocrine systems are an important problem as the basic component of a personalized approach to predicting and treating age-related pathologies. We studied the age-related features of the function of the hypothalamic-pituitary-thyroid axis in laboratory primates with depression- and anxiety-like behavior (DAB). It was found that in young female rhesus monkeys with DAB, the basal and thyrotropin-releasing hormone-stimulated levels of thyroid-stimulating hormone were significantly lower than in young animals with standard behavior (control). During aging, the levels of thyroid-stimulating hormone increased in DAB animals and free thyroxine concentrations decreased both at baseline (fasting) and in response to the thyrotropin-releasing hormone test, while in animals with standard behavior, only a trend towards similar hormonal changes was revealed.

Effect of Constant Illumination on the Function of the Hypothalamic-Pituitary-Adrenal Axis in Nonhuman Primates.

We studied the effect of constant illumination on the effects of administration of arginine vasopressin (AVP), one of the most important regulators of the key adaptive hypothalamic-pituitary-adrenal (HPA) axis under basal conditions and during stress, as well as on the circadian rhythm of activity of HPA axis and the pineal gland in laboratory primates. In young adult female rhesus monkeys exposed to constant illumination for 7 weeks, the rise in the concentration of ACTH and cortisol in response to administration of AVP was markedly reduced in comparison with both the basal period and with the control group of animals. In addition, a destructive effect of constant lighting on circadian rhythm of cortisol secretion was observed in the absence of significant circadian changes in melatonin secretion. The inhibitory effect of constant illumination on the function of the HPA axis under basal conditions and under conditions of its activation can reduce the body's adaptive abilities.

[Features of endocrine function of the pancreas with aging in nonhuman primates with various types of adaptive behavior.]

An increasing number of studies are devoted to the study of the relationship of mental disorders, such as depression and anxiety, with the risk of developing type 2 diabetes mellitus. However, in the literature there are practically no publications on the study of the relationship of the features of higher nervous activity, in particular, adaptive behavior, in healthy individuals with the risk of developing age-related dysfunction of the pancreatic islet apparatus (PIA). The purpose of this study was to investigate features of the functioning of the PIA during aging in individuals with normal standard behavior (SB), as well as anxiety- and depressive-like behavior (DAB) in experiments on nonhuman primates. 76 physically healthy young mature and old female rhesus monkeys with SB and DAB were used in the experiments. Old animals were divided into subgroups with normal (NW) and excess (EW) body weight. All young animals were characterized by NW. The function of PIA was assessed using a glucose tolerance test. Intergroup differences in the functioning of the PIA in young animals were revealed, which were characterized by signs of impaired early insulin response, apparently due to a decrease in the sensitivity of ß-cells of the pancreas to glucose. With aging, the function of the PIA was damaged in all animals, but the features of its changes depended on both the affiliation to a particular behavioral group and the animal's body weight. During aging in animals with SB, the development of relative insulin resistance of peripheral tissues was observed, accompanied by impaired glucose tolerance and a compensatory increase in the secretory activity of the PIA, which were more pronounced in animals with EW. Age-related dysfunction of the PIA in animals with DAB and NW was similar with age-related changes in the PIA function in animals with SB and NW. At the same time, with aging, animals with DAB and EW showed a more significant peak concentration of glucose than that of old animals with SB and EW, accompanied by a minimum «disappearance¼ rate of glucose from the circulation and significantly lower insulin secretion than this in animals with SB and EW. Thus, age-related dysfunctions of the PIA in primates with SB and DAB are unidirectional with the development of insulin resistance, impaired glucose tolerance and a compensatory increase in insulin secretion, which, however, in old animals with DAB and EW are accompanied by exhaustion of the PIA function, increasing the risk of developing type 2 diabetes mellitus.

Effect of Vasopressin V1b Receptor Blockade on Activity of the Hypothalamic-Pituitary-Adrenal Axis in Old Monkeys with Depression-Like and Anxious Behavior Subjected to Stress or Injected with Vasopressin.

The effect of selective antagonist of the arginine vasopressin (AVP) V1b receptors on the secretion of ACTH and corticosteroids in response to insulin-induced hypoglycemia and injection of AVP is studied in old Macaca mulatta females with depression-like and anxious behavior. Intravenous antagonist in a dose of 1.1-1.7 µg/kg inhibits the increase of ACTH concentration, induced by hypoglycemia or injection of AVP. The degree of increase in the concentrations of hydrocortisone and dehydroepiandrosterone sulfate has not changed or increased. The effects of AVP antagonist prove that previously detected disorders in the reaction of the hypothalamic-pituitary-adrenal system in old Macaca mulatta with depression-like and anxious behavior could be caused by excessive activation of vasopressin V1b receptors on the pituitary corticotrophs, while the use of V1b receptor antagonists seems to be a promising method for prevention of these disorders.

Response of the Hypothalamic-Pituitary-Adrenal System to Repeated Moderate Psychoemotional Stress Exposure Is Associated with Behavioral Parameters.

Individual features of the response of the hypothalamic-pituitary-adrenal axis (HPAA) to repeated moderate stress exposure (daily 2-h restraint stress for 10 days) was studied in young female rhesus monkeys with healthy normal behavior and combined group of female rhesus monkeys with abnormal depression-like and anxious behavior. No between-group differences in the response of ACTH and cortisol were found on day 1. On day 10, a rapid and less pronounced increase in ACTH secretion was observed in all animals in comparison with day 1. Analysis of between-group differences in HPAA response showed higher increase in ACTH level and lower increase in cortisol concentration in animals with depression-like and anxious behavior. These changes were similar to the previously described differences in the response of the adenohypophysis and adrenal cortex to acute restraint stress in old monkeys with similar behavior. Thus, individuals with depression-like and anxious behavior demonstrate impaired stress-induced reactivity of HPAA as early as in young age.

Age-specific and individual features of vasopressinergic regulation of the hypothalamic-pituitary-adrenal system in primates.

Experimental study was carried out on young mature (6-8 years) and old (21-27 years) rhesus macaques with anxious and depression-like behavior and with standard (control) adaptive behavior. The responce of the adenohypophysis to arginine vasopressin depended on age and the type of adaptive behavior. Young animals with standard behavior demonstrated much higher concentrations of ACTH in the peripheral plasma in response to arginine vasopressin than old animals. The secretion of ACTH was higher in young and old animals with anxious and depressive-like adaptive behavior and they exhibited no age-specific differences in reaction to arginine vasopressin, which were observed in control animals. Preinjection of vasopressin V1b receptor antagonist to a female with high anxiety sharply reduced ACTH secretion in response to insulin-induced hypoglycemia in comparison with ACTH secretion under the same conditions without antagonist injection. These results suggested that the vasopressinergic system of animals with anxious and depressive behavior plays an important role in the regulation of ACTH secretion and in activity of the hypothalamic-pituitary-adrenal system in general.

[Correction of impaired glucose tolerance using tetrapeptide (Pancragen) in old female rhesus monkeys].

The aim of the investigation was comparative study of the influence tetrapeptide Pancragen (St. Petersburg Institute of Bioregulation and Gerontology, St. Petersburg) on hormonal function of the pancreas compared to the effect of widely used hypoglycemic drug - glimepiride. The investigation involved 9 old (20-25 years) clinically healthy rhesus monkey females (Macaca mulatta). Five of them were injected with Pancragen (0,05 mg/animal per day during 10 days, intramuscularly) for 10 days; 4 animals received glimepiride (4 mg/animal per day during 10 days, per os). Blood samples were taken from all the animals with subsequent analysis of glucose, insulin and C peptide levels; the manipulation was performed before administration of the drugs, on the background of their administration and after their withdrawal in basal conditions, as well as during glucose tolerance testing. Pancragen and glimepiride administration induced the decrease of blood glucose basal levels in both groups of old monkeys. Pancragen also normalized insulin and C peptide levels suggesting its recovering effect on the disturbed tolerance to glucose in old animals. At the same time, glimepiride administration led to a more expressed and delayed hypoglycemic effect and C peptide secretion stimulation without any significant effect on insulin secretion. The data suggest that Pancragen is effective and safe for correction of age-related imbalance of endocrine pancreatic function, and can be used for elderly patient with disturbed glucose tolerance.

Effect of aging on stress reactivity of the adrenal cortex in laboratory primates. Dependence on the time of day.

Age-specific differences in the reaction of the hypothalamic-pituitary-adrenal system to acute psychoemotional stress (immobilization) was studied in female rhesus macaques aged 6-8 and 20-27 years at different time of the day. The reactivity of the hypothalamic-pituitary-adrenal system during immobilization at 15.00 was lower in old animals, while at 9.00 there were no age-specific differences or the reactivity was higher in old animals.

Age-associated changes in hormonal function of the pancreas and regulation of blood glucose in monkeys.

Age-associated changes in the concentrations of glucose, insulin, and DHEAS in peripheral blood plasma of female rhesus macaques were studied in intact animals and in response to a standard dose of glucose and insulin. Basal levels of insulin and glucose increased, insulin sensitivity and glucose tolerance decreased, and pancreatic reaction to glucose load was impaired in old monkeys. Insulin level positively correlated with glucose concentration, body weight, and abdomen circumference and negatively correlated with DHEAS level.

Functions of the hypothalamo-hypophyseal-adrenal system in aging in female monkeys.

Comparative studies on the functioning of the adrenal cortex in female rhesus macaques (Macaca mulatta) of different ages are reported - animals were aged 6-9 years (young adults; n = 5) and 20-26 years (old adults; n = 5). Corticosteroid concentrations (cortisol (F) and dehydroepiandrosterone sulfate (DHEAS)) were determined by specific radioimmunological and immunoenzyme methods in basal conditions, after acute stress (insulin-induced hypoglycemia, 2-h movement restriction), and after administration of dexamethasone. Basal F levels showed no marked age differences, while DHEAS concentrations in older animals decreased sharply. These animals also demonstrated weakened adrenal cortex responses to movement restriction, giving rise to delays in reaching peak F and DHEAS levels and decreases in the areas under their response curves (AUC) during the 4-h study period. In the dexamethasone test, the hypothalamo-hypophyseal-adrenal system of monkeys aged 20-26 years was relatively resistant to the suppressing effect of glucocorticoids via the negative feedback mechanism. It is suggested that disruption of feedback in the system controlling adrenal cortex function may be at least partially due to the development of peripheral blood steroid dysbalance with aging, this consisting particularly of a decrease in the DHEA (DHEAS) level; this steroid is known for its neurological activity.

Antibodies reacting with human T-lymphotropic retrovirus (HTLV-I) or related antigens in lymphomatous and healthy hamadryas baboons.

The sera of lymphomatous and healthy hamadryas baboons of the main, lymphoma-prone Sukhumi stock were tested for antibodies reacting with HTLV-I antigens in the indirect immunofluorescence test. Antibodies of this specificity were found in all but one of 58 lymphomatous baboons and in 45% of 177 healthy ones. The prevalence of HTLV-I reactive antibodies in lymphoma-free baboon populations (including 118 Sukhumi "forest" stock animals and 195 baboons imported in 3 groups from Ethiopia) was consistently lower (5-8%). The specificity of baboon antibodies reacting with HTLV-I or a related agent is supported by the following evidence: Concordant reactivity pattern of baboon sera with several HTLV-I-positive and-negative human cell lines; elimination of baboon sera anti-HTLV reactivity by absorption with purified HTLV-I, but not by other retroviruses; significant correlation between immunofluorescence titers of baboon sera and their reactivity in enzyme-linked immunosorbent assay with purified HTLV-I; competition of baboon anti-HTLV with monoclonal antibodies GIN-14 for binding of the epitope on p19HTLV-I. The prevalence of anti-HTLV positives in the main Sukhumi stock increased by age, reaching its maximum (approx. 80%) at 5-15 years, and showed no significant sex-related variation. The level of anti-HTLV antibodies in lymphomatous baboons and in age-, sex- and population-matched healthy ones did not differ. However, in pre-lymphoma sera these antibodies reached significantly higher levels than in sera of lymphomatous baboons (obtained in the terminal stage) or of matched, healthy controls.