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There are several interrelated mechanisms involving iron, dopamine, and neuromelanin in neurons. Neuromelanin accumulates during aging and is the catecholamine-derived pigment of the dopamine neurons of the substantia nigra and norepinephrine neurons of the locus coeruleus, the two neuronal populations most targeted in Parkinson's disease. Many cellular redox reactions rely on iron, however an altered distribution of reactive iron is cytotoxic. In fact, increased levels of iron in the brain of Parkinson's disease patients are present. Dopamine accumulation can induce neuronal death; however, excess dopamine can be removed by converting it into a stable compound like neuromelanin, and this process rescues the cell. Interestingly, the main iron compound in dopamine and norepinephrine neurons is the neuromelanin-iron complex, since neuromelanin is an effective metal chelator. Neuromelanin serves to trap iron and provide neuronal protection from oxidative stress. This equilibrium between iron, dopamine, and neuromelanin is crucial for cell homeostasis and in some cellular circumstances can be disrupted. Indeed, when neuromelanin-containing organelles accumulate high load of toxins and iron during aging a neurodegenerative process can be triggered. In addition, neuromelanin released by degenerating neurons activates microglia and the latter cause neurons death with further release of neuromelanin, then starting a self-propelling mechanism of neuroinflammation and neurodegeneration. Considering the above issues, age-related accumulation of neuromelanin in dopamine neurons shows an interesting link between aging and neurodegeneration., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The pineal and pituitary-adrenocortical secretions play an important role in adaptive responses of the organism acting as coordinating signals for both several biological rhythms and multiple neuroendocrine and metabolic functions. The more relevant neuroendocrine changes occurring with ageing affect the secretion of melatonin and of corticosteroids. These changes may be clearly appreciated by the study of their circadian rhythmicity. The circadian profile of plasma melatonin was clearly flattened in elderly subjects and even more in old individuals with dementia. Indeed, the impairment of melatonin signal occurring in aging was related either to age itself or to the cognitive performances of subjects. The biosynthetic dissociation between glucocorticoids and androgen secretion is responsible for the selective impairment of androgens, such as DHEA and DHEA-S, by comparison to cortisol. Due to the opposite effects of the two kinds of corticosteroids either in the periphery and in the CNS, the imbalance between glucocorticoids and androgens, well demonstrated by the evaluation of the cortisol/DHEA-S molar ratio, may be responsible for the occurrence in the CNS of a more neurotoxic steroidal milieu, already present in clinically healthy elderly subjects and especially in patients with dementia. The effects of that steroidal milieu are more prominent at the level of the hippocampal-limbic structure, involved both in the modulation of endocrine structures, such as the HPA axis, and in the control of cognitive, behavioral and affective functions.

Patients age has been estimated in healthy population by means of the heart rate variability (HRV) parameters to assess the potentiality of HRV indexes as a biomarker of age. A long-term analysis of HRV has been performed, computing linear time and frequency domain parameters as well as non-linear metrics, in a dataset of 113 healthy subjects (age range 20-85 years old). The principal component analysis has been used to capture age-related influence on HRV and then three different models have been applied to predict subjects age: a robust linear regressor (RLR), a feedforward neural network (FFNN) and a radial basis function neural network (RBFNN). A good prediction of patient age has been obtained (using all principal components, the Pearson correlation coefficient between predicted and real age: RLR=0.793; FFNN=0.872; RBFNN=0.829), even if an overestimation in younger subjects and an underestimation in older ones may be observed. The important and complementary contribution of non-linear indexes to aging related HRV modifications has also been underlined.

In this study, a comparison between elderly (>70 years) and young subjects reveals that elder people are subject to a higher oxidative stress, which causes an increase in plasma hydroperoxide levels (18%) and a decrease in antioxidant defenses (25%). Moreover, the marked decrease of the erythrocyte membrane fluidity observed in elderly subjects was likely to affect the behavior of some membrane glycohydrolases. In fact, a significant decrease of beta-d-glucuronidase and neutral sialidase (30 and 50%, respectively) was detected. Activity differences were also observed when erythrocytes were further distinguished according to their biological age. Striking differences between young and elderly subjects were observed for beta-d-glucuronidase and neutral sialidase in young and senescent erythrocytes, respectively. Overall beta-d-glucuronidase decreases with the subjects' age, while neutral sialidase levels are higher in the elderly. This is presumably due to the localization of these enzymes in distinct plasma membrane micro-domains, which are differently peroxidized. A possible role of these enzymes in signaling praecox membrane alterations has also been evidenced.

Melatonin secretion is an endogenous synchronizer, and it may possess some anti-aging properties. Thus we examined melatonin levels in physiological aging, in extreme senescence and in senile dementia. In healthy old (age 66-94 yr) and young subjects (age 23-39 yr) and in demented patients (age 68-91 yr) plasma melatonin was measured by radioimmunoassay in eight serial blood samples. In centenarians (age 100-107 yr) melatonin levels were estimated by assaying urinary 6-hydroxymelatonin sulfate (aMT6s) in two different urine samples collected from 08:00 to 20:00 hours and from 20:00 to 08:00 hours. These data were compared with the aMT6s excretion of old and young controls. Elderly subjects, demented or not, exhibited a flattened circadian profile of plasma melatonin, because of the suppression of the nocturnal peak. An age-related decline of the circadian amplitude of the melatonin rhythm occurred in old subjects, especially in demented individuals. Furthermore, the melatonin nocturnal peak was significantly correlated with the severity of the cognitive impairment. aMT6s urinary excretion also declined with age. However, as in young controls, in centenarians the aMT6s excretion was significantly higher at night than during the day. In conclusion, pineal melatonin secretion is affected by age and by the degree of cognitive impairment. In centenarians the maintenance of the circadian organization of melatonin secretion may suggest that the amplitude of the nocturnal peak and/or the persistence of a prevalent nocturnal secretion may be an important marker of biological age and of health status.

Age-related structural and neurochemical changes occurring in the central nervous system have been related to changes in some rhythmometric parameters. In spite of their clinical importance, only a few studies have investigated the modifications over time of serum electrolytes in senescence. The aim of our study was to evaluate the circadian pattern of serum potassium, chloride, sodium, calcium and phosphorus in 30 clinically healthy elderly subjects, with no cognitive impairment, and to compare the findings with those given by 24 healthy young controls. The subjects were synchronized as regards their daily activities, sleeping/waking habits, time/quality of meals and dietary electrolyte intake. After an overnight fast, samples were taken beginning at 08.00 and every 4 h thereafter until 20.00, and every 2 h from 20.00 to 04.00. Both the young and the elderly subjects exhibited statistically significant circadian rhythms for all serum electrolytes considered. Our findings suggest that circadian organization of serum electrolytes is maintained in physiological aging, even though it should be noted that sodium and phosphorus acrophases differed significantly in the two experimental groups.

Background and Aims: Changes in some rhythmometric parameters have been reported in the elderly as a consequence of both structural and neurochemical changes occurring in the central nervous system. Since alterations of lipid and lipoprotein metabolism are directly involved in several age-related disorders, the aim of this study was to investigate the circadian temporal organization of some important lipidic fractions (total cholesterol, triacylglycerol, apolipoprotein A1 and B) in physiological aging., Methods: Thirty old hospitalized subjects were synchronized for daily activities, sleeping/waking habits, and time/quality of meals. Twenty-four healthy young individuals served as controls. After an overnight fast, samples were taken beginning at 08:00 every 4 hours until 20:00, and every 2 hours from 20:00 to 04:00. Rhythmometric data were analyzed by single and population mean Cosinor analysis, and by ANOVA; the comparison of the rhythm's parameters between elderly and young subjects was carried out by the Mesor test and the amplitude-acrophase using Hotelling's test., Results: Elderly subjects exhibited statistically significant circadian rhythms for total cholesterol (p<0.00002), triacylglycerol (p<0.000001), apo A-1 (p<0.0013), and apo B (p

Changes in thyroid function are often described in elderly subjects; however, their pathophysiologic significance and the possible contributory role of both malnutrition and nonthyroidal illness are still debated. The aim of this cross-sectional study was to investigate thyroid function in relationship to some markers of the nutritional status in a group of healthy old subjects and in some centenarians living in nursing homes. Patients included 24 clinically healthy elderly women (age, 71 to 93 years), 24 clinically healthy centenarian women (age, 100 to 106 years), and 20 healthy young subjects (age, 22 to 33 years). Blood samples were drawn from each subject for the evaluation of thyroid-stimulating hormone (TSH), free triiodothyronine (FT(3)), free thyroxine (FT(4),) reverseT(3) (rT3), autoantibodies against thyroglobulin (AbTg) and against thyroid peroxidase (AbTPO), and for the main humoral nutritional markers. TSH and thyroid hormones were assayed by fluoroimmunometric method; rT3 and thyroid autoantibodies by radioimmunoassay (RIA) and enzyme chemiluminescent immunometric assay, respectively. The mean values of TSH, FT(3) and FT(4) fell within the normal range in both groups. However, by comparison to old controls, in centenarian subjects, TSH levels were significantly lower, whereas rT(3) concentrations were slightly, but significantly, increased. Autoantibodies positivity was found in 4.16% of centenarians and in 10.4% and 13.6% of old and young controls. Thus, the incidence of thyroid autoantibodies was lower in centenarians than in old controls. Except for transferrin, lower than the normal range in centenarians, all of the other nutritional markers evaluated fell within the laboratory range of normality. Total cholesterol levels were significantly reduced in centenarians by comparison to old controls. Our results showed an age-related decline of the TSH levels and a significant increase of the rT(3) concentrations in centenarians by comparison to old controls. These findings may be related to an age-dependent reduction of the 5'-deiodinase activity rather than to important changes of nutritional markers., (Copyright 2002 by W.B. Saunders Company)

The biosynthetic dissociation of the adrenocortical secretion occurring with age may have a pathogenetic role in the pathophysiology of brain aging. We studied cortisol and DHEAS secretion in healthy old and young subjects, in senile dementia, in major depression of elderly subjects and in healthy centenarians. A clear age-related decline of DHEAS secretion was well evident in healthy centenarians, and a further decrease in DHEAS concentration was found in old depressed patients and moreover in the demented ones, by comparison with age-matched controls. The circadian profile of serum cortisol was clearly flattened in old subjects, due to the selective increase in the cortisol nocturnal levels, particularly evident in demented subjects; on the other hand, the morning serum cortisol levels were not significantly different among centenarians, young and old controls. The molar ratio between cortisol and DHEAS showed a significant age-related increase; the occurrence of senile dementia and of major depression played an additive role, by comparison to physiological aging. The qualitative and quantitative modifications of the adrenocortical secretion occurring with aging seem mainly dependent on age itself, but the occurrence of pathological conditions may amplify these changes. Since cortisol and DHEAS play opposite effects on the central nervous system, the evaluation of the ratio between cortisol and DHEAS seems to be a good marker of the neuroendocrine features in old subjects.

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.

The simultaneous evaluation of the circadian rhythm of plasma melatonin and ACTH and of serum cortisol and DHEAS represents a clinically reliable tool to appreciate the neuroendocrine changes occurring in physiological and pathological brain aging.A selective impairment of the nocturnal melatonin secretion has been observed in elderly subjects, being significantly related either to the age or to the severity of dementia. A significant increase of serum cortisol levels during evening- and night-times was found in elderly subjects, particularly if demented, when compared to young controls. Besides, both the circadian amplitude of cortisol rhythm and the nocturnal cortisol increase were significantly reduced in relation either to age or to cognitive impairment. By comparison to vascular dementia, patients with Alzheimer's disease exhibited the highest cortisol concentrations throughout the 24h. The sensitivity of the hypothalamic-pituitary-adrenal axis to the steroid feedback was significantly impaired in old subjects and particularly in the demented ones. The serum DHEAS levels were significantly lower in elderly subjects and even more in demented patients than in young controls. Consequently, a significant increase of the cortisol/DHEAS molar ratio was evident when going from young controls to healthy elderly subjects and to demented patients. In conclusion, the aging process affects many neuroendocrine functions resulting in subtle but clinically relevant consequences; the occurrence of senile dementia seems to play an additive role.

Aging is associated with a selective decline in circulating levels of dehydroepiandrosterone (DHEA) and its sulfate, with no major changes in cortisol secretion. In young subjects, serum levels of both DHEA and cortisol are regulated according to a circadian rhythm, and an age-related attenuation of DHEA, but not cortisol, circadian rhythmicity has been reported. Several trials have evaluated the effects of DHEA supplementation in elderly subjects, although the results are still controversial. However, no data are available on the 24-hour profile of DHEA circulating levels in elderly subjects with DHEA administration. In the present study, we evaluated the circadian rhythms of DHEA, cortisol, and the cortisol/DHEA molar ratio in old subjects treated with either placebo (old-PL) or a single 50-mg dose of DHEA (old-D), both administered orally at 0700 hours. For each variable, the circadian profiles were compared with those obtained in young control subjects. The group of young subjects displayed a circadian rhythm for both DHEA and cortisol serum concentrations but no rhythm for the cortisol/DHEA molar ratio. In the old-PL group, the circadian rhythm of DHEA was completely abolished, whereas significant rhythms for both cortisol and the cortisol/DHEA molar ratio were observed. Particularly, at each time point, the cortisol/DHEA molar ratio was significantly higher in these subjects versus the young group. In the old-D group, the circadian rhythm of DHEA was completely restored and was comparable to that observed in the young group. Analogous to the observations in young subjects, the profile of the cortisol/DHEA molar ratio in old-D subjects did not display any circadian rhythmicity, the values being almost completely comparable to those observed in young controls. Our data demonstrate that the circadian rhythm of DHEA is totally abolished in elderly subjects. A single 50-mg dose of DHEA administered orally at 0700 hours restores the circadian rhythmicity of serum DHEA and almost completely normalizes the 24-hour profile of the cortisol/DHEA molar ratio in old subjects without affecting the cortisol circadian rhythm.

The circadian organization of adrenal secretion was studied in 23 healthy elderly subjects, 23 elderly demented patients and 10 healthy young subjects, in order to investigate the relationships between the hypothalamic-pituitary-adrenal axis and some cerebral morphometric parameters. The cerebral morphometric analysis was performed in some subjects of the three groups by MRI. A significant increase in cortisol levels during evening and nighttime was found in both groups of the aged subjects. In elderly subjects, particularly if demented, the mean serum dehydroepiandrosterone sulfate (DHEAs) levels throughout the 24-hour cycle were significantly lower than in young controls. A significant reduction of the hippocampal and temporal volume and an enlargement of the lateral ventricles were found in aged subjects, these changes being significantly related to subjects' age. Moreover, the hippocampal volume was positively correlated with the circadian mesor of DHEAs (i.e., the circadian rhythm adjusted mean) and with the cortisol nocturnal increase. Our data may suggest the existence of a link between the selective impairment of cortisol secretion and DHEAs levels, and the progression of hippocampal degeneration., (Copyright 2000 S. Karger AG, Basel)

A link between neuroendocrine and immunological changes has been suggested in the pathophysiology of dementia of the Alzheimer's type (DAT). Healthy young and old subjects and patients with DAT were recruited to evaluate the chrononeuroendocrine organization of cortisol, GH, and melatonin (MLT) secretions. The study was carried out together with the evaluation of natural killer (NK) cell function: cytotoxic activity (NKCC) and TNF-alpha and IFN-gamma release after exposure to IL-2 (100 U/mL). Moreover, a cerebral morphometric analysis of hippocampus and temporal lobe (MRI) was performed. The activation of hypothalamo-pituitary-adrenal (HPA) axis and the decrease of GH, and MLT nocturnal peaks were associated with normal NKCC and TNF-alpha/IFN-gamma in healthy elderly subjects, whereas in DAT patients the same neuroendocrine changes occurred together with abnormal NKCC (spontaneous and IL-2/IFN-beta-modulated) and with alterations of TNF-alpha/INF-gamma generation from NK. Moreover significant correlations among the increase of NKCC and TNF-alpha and the decrease of cognitive function were found in the DAT group. These correlations were associated with the impairment of nocturnal GH and MLT levels and with the relatively higher serum cortisol concentrations. Moreover, the impairment of cortisol suppression after dexamethasone (1 mg orally at 23:00) was significantly correlated with the increase of spontaneous release of TNF-alpha and with IL-2-modulated NKCC. Finally the imunoneuroendocrine alterations found in DAT were associated with the reduction of cerebral volume in hippocampus and temporal lobes. Taken together these data indicate that the immunoneuroendocrine balance is maintained in physiological aging, whereas NK immune dysregulation in DAT could contribute to altering the neuroendocrine functions and to extend the progression of neurodegeneration and dementia.

Allopregnanolone is the best characterized among neurosteroids, and its role in the control of neuroendocrine axes has attracted increasing interest recently. However, there is no available information about circulating levels of allopregnanolone during infancy, childhood and puberty. We studied two groups of children: 1) those aged between 0 and 2 y (n = 72), and 2) those aged between 6 and 18 y, at different Tanner's stages (n = 82). In each of these patients, serum allopregnanolone, progesterone, cortisol, and dehydroepiandrosterone levels were evaluated after informed consent; allopregnanolone was measured by RIA after acid extraction on cartridge. There was no significant variation of serum allopregnanolone levels either in male and female children during the first 2 y of life. Furthermore, although serum dehydroepiandrosterone levels showed a significant decrease, inversely correlated with age of the children (p < 0.01), serum cortisol and progesterone levels showed a significant age-related increase during the first 2 y of life. Cortisol and allopregnanolone levels were positively correlated (p < 0.01). During puberty, we observed a progressive increase in serum allopregnanolone levels in both boys and in girls, which were higher at Tanner' s stage IV-V (0.7+/-0.01 nM; mean +/- SEM) than at stages I-II (0.32+/-0.02 nM; p < 0.01); mean levels were significantly higher at puberty than in the first 2 y of life (p < 0.01). Furthermore, during puberty, serum progesterone and dehydroepiandrosterone levels also increased progressively with age in both boys and girls. Allopregnanolone and dehydroepiandrosterone levels were positively correlated throughout puberty. The present results indicate that serum allopregnanolone levels do not change during the first 2 y of life but increase during pubertal development, suggesting that this steroid may be involved in the adaptive neuroendocrine mechanisms related to puberty.

Experimental and clinical investigations suggest the hypothesis that dehydroepiandrosterone sulfate (DHEAS) can positively influence natural killer (NK) immunity via locally produced insulin-like growth factor I (IGF-I) from NK cells. In the present study, the NK cell cytotoxicity (NKCC) and IGF-I levels in the supernatant of NK cells were studied at baseline and after exposure to various molar concentrations of DHEAS (from 10(-5)-10(-8) mol/L x mL/7.75 x 10(6) NK cells) in healthy subjects of young and old age. DHEAS-induced NKCC was also determined after DHEAS coincubation with somatostatin-14 (10-6) mol/L x mL/7.75 x 10(6) NK cells) and with interleukin-2 (IL-2; 100 IU/mL x 7.75 x 10(6) NK cells). NK cells were previously isolated by Ficoll-Hypaque density gradient and then by immunomagnetic procedure; the purity obtained was 97 +/- 1%. NKCC was determined against K562 tumoral targets. We observed that the increase in NKCC after DHEAS exposure was dose dependent and was correlated with the amount of IGF-I released in the supernatant of cultured NK cells. NKCC and IGF-I generation from NK cells were more elevated in healthy elder subjects than in healthy young subjects. The coincubation of DHEAS with somatostatin-14 significantly suppressed NKCC and IGF-I release from NK in both groups, whereas higher NKCC was found after DHEAS plus IL-2 exposure than after incubation with DHEAS alone. Taken together, this study suggests a role for NK-generated IGF-I in the modulation of NKCC by DHEAS in humans. Although DHEAS may contribute to the IL-2-mediated NKCC, its activity on NK cytolytic function can be dependent on a autocrine mechanism (IGF-I-mediated), probably independent of cytokine activation. The higher NKCC response to DHEAS found in old subjects than in younger might counterbalance the age-dependent decline in circulating DHEAS, thus contributing to maintain the pattern of NK immunity during aging.

Background: It is well known that nutritional status and CNS functions are closely related. Malnutrition leads to an impaired cognitive performance, and mental disturbances may be responsible for alterations in eating behaviour. The correlation between nutritional and cognitive status seems to be even closer in the elderly because of the higher incidence of neuropsychic syndromes and malnutrition., Methods: Given this background, we set up this study in order to correlate cognitive status (investigated using the Mini-Mental State Examination--MMSE--and the Geriatric Depression Scale--GDS) and various biochemical nutritional indicators (serum electrolytes, albumin, transferrin, erythrocytes, lymphocyte count, hematocrit, hemoglobin, total cholesterol, HDL cholesterol, triglycerides and total proteins) in 82 apparently healthy elderly people (mean age +/- SD 87 +/- 6)., Results: Our data demonstrated a correlation between the MMSE score (26 +/- 2) and Na (138.1 +/- 3.0 mmol/L, r = -0.66, p < 0.001) and Cl (102.4 +/- 4.5 mmol/L, r = -0.62, p < 0.001) serum electrolytes, but no correlation with the other nutritional data. The demonstrated relationship does not appear to be causal because Na and Cl are chemically and physiologically linked., Conclusions: These correlations underline the relevance of the correct intake and metabolism of electrolytes for functional CNS activity in the elderly.

We studied the circadian rhythm of plasma melatonin, growth hormone (GH), prolactin (PRL), adrenocorticotropic hormone (ACTH), and cortisol in 52 mentally healthy old subjects, 35 old demented patients, and 22 clinically healthy young controls. When compared to young controls, the circadian profile of plasma melatonin of old subjects, both demented or not, was clearly flattened, particularly during the night. The selective impairment of nocturnal melatonin secretion was significantly related to both the age and the severity of mental impairment (Mini Mental State Examination [MMSE] score). The PRL and GH circadian profiles were similar in the three groups during the day, but a significant lowering of the values recorded during the night occurred with aging. The impairment of the nocturnal secretion was related to the subjects' age and, for the GH secretory pattern only, also to the MMSE score. The ACTH circadian profile was similar in the three groups studied, even when old subjects exhibited higher ACTH levels throughout the 24 h cycle, compared to young controls. Significantly higher cortisol values at evening- and nighttime occurred in elderly subjects and particularly in the demented group. Both the mean levels and the nadir values of plasma cortisol were positively related to age and negatively to MMSE score. In order to verify the sensitivity of the hypothalamo-pituitary-adrenal (HPA) axis to the steroid feedback, the circadian profile of plasma cortisol was evaluated also after dexamethasone (DXM) administration (1 mg at 23:00 h); the sensitivity of the HPA axis was significantly impaired in old subjects and particularly in the demented ones. These findings suggest that the neuroendocrine alterations already present in physiological aging, due to both anatomical damages and unbalanced central neurotransmitters, are enhanced in senile dementia.

To understand the magnitude of oxidative phenomena during senescence, we evaluated, as antioxidant, the activity of glutathione peroxidase (GSH-Px) in erythrocytes and plasma uric acid (UA) levels together with the malondialdehyde (MDA) levels in plasma, as an index of lipid peroxidation, in 46 apparently healthy elderly subjects (87 +/- 6 years old; mean +/- SD), and 49 young subjects (29 +/- 4 years old). The elderly subjects had lower erythrocyte GSH-Px activity (15.7 +/- 4.8 vs 20.2 +/- 7.0 U/g Hb, p < 0.001; mean +/- SD) and plasma UA levels (192 +/- 46 vs 240 +/- 54 mmol/L, p < 0.001), but higher MDA levels (5.3 +/- 0.8 vs 4.1 +/- 0.8 mmol/L, p < 0.001) than the young subjects. Of additional interest was the finding of a positive correlation between age and erythrocyte GSH-Px activity (r = 0.74, p < 0.001), and a negative correlation between age and plasma MDA levels (r = -0.83, p < 0.001) in the elderly group. Although erythrocyte (GSH-Px activity was significantly less in the elderly than in the young group, the oldest subjects showed the greatest erythrocyte GSH-Px activity and had lower MDA levels.

The study of the neuroendocrine changes occurring in aging may give information about the CNS functions, and also explain the impaired plasticity of the aged organism. In 16 elderly women and in 14 young controls, the circadian rhythms of plasma melatonin, GH, PRL, ACTH and cortisol, and of oral temperature were simultaneously studied. The plasma cortisol circadian rhythm was also evaluated after DXM administration (1 mg orally at 23:00). The circadian profile of all the bioperiodic functions evaluated was clearly flattened in elderly subjects, and an impairment of the hormonal nocturnal secretion of GH, PRL and melatonin was apparent in elderly subjects when compared to young controls. The plasma ACTH levels throughout the 24-hour cycle were significantly higher in elderly than in young subjects. The cortisol circadian profile exhibited significantly higher values in the evening- and night-time in elderly subjects, compared to young controls; the cortisol nadir values were significantly age-related. A reduction of the sensitivity to DXM inhibition occurred in the elderly group. Both the selective impairment of nocturnal melatonin secretion, and the reduction of hypothalamo-pituitary-adrenal (HPA) sensitivity to steroid feed-back might be considered as markers of aging brain. The neuroendocrine alterations of physiological aging may be ascribable to both the structural and neurochemical changes occurring in the CNS.

Physiological brain aging is characterized by important biochemical and structural changes and by the unbalance among the different neurotransmitters and neuromodulators. The study of the circadian organization of neuroendocrine functions may be considered a clinically reliable tool to investigate the changes of the CNS and particularly of the limbic-hypothalamic system occurring in aged people. The circadian rhythms of plasma melatonin, ACTH and cortisol and of oral temperature were studied in 16 clinically healthy women aged 66-90 years and in 14 young controls aged 20-30. In addition, the effect of dexamethasone on the plasma cortisol circadian rhythm and the cortisol response to Synacthen pulse intravenous injection were evaluated. All subjects were studied as inpatients, with the same synchronization to the hospital life schedule. When compared with young controls, elderly subjects exhibited a reduction of the mean level and of the amplitude of the circadian rhythm of oral temperature, an increase of the mean level of ACTH and cortisol rhythms and a selective impairment of melatonin nocturnal secretion. Furthermore, elderly subjects showed a reduced sensitivity to the dexamethasone suppression test, by comparison to young controls. These changes were age-related and they may depend either on CNS modification or on alterations of the hormonal metabolic clearance.

The circadian pattern of melatonin and cortisol secretion was evaluated in two groups of elderly subjects (aged 66-90 years), one with Alzheimer's type of multiinfarct dementia (n = 27) and the other without cognitive impairment (n = 16); 13 clinically healthy women aged 20 to 30 years were chosen as controls. All demented patients had severe mental impairment, corresponding to stage 6 of the Global Deterioration Scale. All subjects, either young or aged, were studied as in-patients and were well synchronized with respect to meal timing, diurnal activity and nocturnal rest. At the population mean cosinor analysis (Halberg, 1969) both melatonin and cortisol circadian rhythms reached statistical significance in the three groups of subjects. However, the melatonin circadian profile was clearly flattened in the two groups of elderly subjects by comparison with young controls, due to the selective impairment of melatonin nocturnal secretion. In both elderly groups, but particularly in demented patients, plasma cortisol levels were significantly higher by comparison to young controls, particularly at evening and night time. A significant direct relationship linked the subjects' age and the nadir values of plasma cortisol. Furthermore, the sensitivity of the hypothalamo-pituitary-adrenal axis to dexamethasone (DXM) suppression test (1 mg orally at 2300) was significantly reduced in both elderly groups, and especially in old demented patients, by comparison with young controls. Finally, plasma cortisol response to pulse i.v. injection of a small dose of synthetic corticotropin (Synacthen 2,500 ng) was significantly higher and more prolonged in old demented patients than in mentally healthy old subjects and in young controls.(ABSTRACT TRUNCATED AT 250 WORDS)

This paper addresses the difficult problem of predicting service life in pressureless underground plastics pipes applications. Lifetime in such applications is generally determined by thermooxidative behaviour, which is governed principally by the type and amount of two classes of stabiliser: primary antioxidants and thio-synergistics. Ageing studies in water at 95°C have indicated that, for polypropylene (PP), mechanical performance is not influenced by exposure for up to six months (longer term trials are in progress). Despite this, aging in water can have a significant effect on the thermoxidative life of PP, by extracting antioxidant additives. As in pressurised pipe applications, determination of the combined effects of oxygen and water extraction is key to useful predictions of durability. In an attempt to improve life assessment, polypropylene plaques have been aged in contact with water at 95°C to determine the fitting parameters for Fickian diffusion. The residual stabiliser was measured directly by high-performance liquid chromatography (HPLC) and indirectly, using oven aging. Parameters have been determined for three phenolic primary antioxidants widely used in polyolefin pipes. Direct analysis by HPLC was found to give much lower scatter and hence is proposed as the more reliable method. A methodology is proposed to predict the lifetime of polyolefin pipe materials for underground sewerage applications avoiding the need to make tests on pipes. [ABSTRACT FROM AUTHOR]