Serum dehydroepiandrosterone (DHEA) and DHEA sulfate are negatively correlated with serum interleukin-6 (IL-6), and DHEA inhibits IL-6 secretion from mononuclear cells in man in vitro: possible link between endocrinosenescence and immunosenescence

Interleukin-6 (IL-6) is one of the pathogenetic elements in inflammatory and age-related diseases such as rheumatoid arthritis, osteoporosis, atherosclerosis, and late-onset B cell neoplasia. In these diseases or during aging, the decrease in production of sex hormones such as dehydroepiandrosterone (DHEA) is thought to play an important role in IL-6-mediated pathogenetic effects in mice. In humans, we investigated the correlation of serum levels of DHEA, DHEA sulfate (DHEAS), or androstenedione (ASD) and IL-6, tumor necrosis factor-alpha, or IL-2 with age in 120 female and male healthy subjects (15-75 yr of age). Serum DHEA, DHEAS, and ASD levels significantly decreased with age (all P < 0.001), whereas serum IL-6 levels significantly increased with age (P < 0.001). DHEA/DHEAS and IL-6 (but not tumor necrosis factor-alpha or IL-2) were inversely correlated (all patients: r = -0.242/-0.312; P = 0.010/0.001). In female and male subjects, DHEA and ASD concentration dependently inhibited IL-6 production from peripheral blood mononuclear cells (P = 0.001). The concentration-response curve for DHEA was U shaped (maximal effective concentration, 1-5 x 10(-8) mol/L), which may be the optimal range for immunomodulation. In summary, the data indicate a functional link between DHEA or ASD and IL-6. It is concluded that the increase in IL-6 production during the process of aging might be due to diminished DHEA and ASD secretion. Immunosenescence may be directly related to endocrinosenescence, which, in turn, may be a significant cofactor for the manifestation of inflammatory and age-related diseases.     

Reproductive senescence predicts cognitive decline in aged female monkeys

The present investigation provide evidences from a non-human primate model that naturally occurring menopause predicts a prominent signature of age-related cognitive decline. Young and aged rhesus monkeys were tested on a delayed response (DR) task known to the sensitive to aging, and reproductive status was evaluated according to menstrual cyclicity and urinary hormone profiles. Peri-/postmenopausal monkeys exhibited significant DR impairments relative to either age-matched premenopausal females, or young control subjects. In addition, markers of endocrine decline in the aged animals were selectively correlated with behavioral performance measures that distinguished premenopausal and peri-/postmenopausal monkeys. These results document that menopause is coupled to cognitive decline in the monkey, and they establish a valuable primate model for defining the effects of endocrine aging on brain and behavioral function.     

Effects of age on cerebrospinal fluid oxytocin levels in free-ranging adult female and infant rhesus macaques.

There is growing interest in examining oxytocin and social functioning in human and non-human primates. Studies of human oxytocin biology are typically restricted to peripheral assessments because opportunities to collect cerebrospinal fluid (CSF) are rare. Several studies have examined CSF oxytocin levels in captive adult primates, but none to our knowledge have been conducted under free-ranging conditions and inclusive of infants. The main goal of this study was to establish feasibility of quantifying CSF oxytocin levels in free-ranging adult female and infant rhesus monkeys living on Cayo Santiago, PR. CSF oxytocin levels were examined in relation to individuals' demographic and reproductive characteristics as well as plasma cortisol levels. CSF oxytocin concentrations ranged from 36.02 to 134.41 pg/ml in adult females (ages 7–26 years; N = 31) and 35.94 to 77.3 pg/ml in infants (ages 38–134 days; N = 17). CSF oxytocin levels were positively correlated with adult female age and negatively correlated with infant age. The former correlation was driven by reproductive status. CSF oxytocin levels were unrelated to dominance rank or plasma cortisol levels. In contrast to a previous study of plasma oxytocin concentrations in this population, CSF oxytocin levels did not differ significantly between lactating and non-lactating females. These findings: 1) provide feasibility data for examining CSF oxytocin levels in free-ranging non-human primates and 2) indicate that CSF oxytocin levels may be a biomarker of age-related central nervous system changes across lifespan development. Research is now required to examine CSF oxytocin levels in the context of social functioning in free-ranging rhesus monkeys. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Antioxidant activity of dioscorea and dehydroepiandrosterone (DHEA) in older humans

Dioscorea is a yam steroid extract used in commercial steroid synthesis and consumed by people. DHEA is a steroid which declines with age, but without known activity. This study was designed to determine whether dioscorea supplementation could increase serum dehydroepiandrosterone sulfate (DHEAS) in humans and modulate lipid levels in older people. The subjects were selected volunteers aged 65-82 years. The serum DHEAS level, lipid peroxidation and lipid profile were assessed. Three weeks of dioscorea supplementation had no affect on serum DHEAS level. However DHEA intake of 85 mg/day increased serum DHEA levels 100.3%. DHEA and dioscorea significantly reduced serum lipid peroxidation, lowered serum triglycerides, phospholipid and increased HDL levels. Both DHEA and the steroid yam extract, dioscorea, have significant activities as antioxidant to modify serum lipid levels.     

A strategy for identifying biomarkers of aging: further evaluation of hematology and blood chemistry data from a calorie restriction study in rhesus monkeys

We examined a dataset derived from a battery of hematology and blood chemistry tests to identify candidate biomarkers of aging in a sample of 33 male rhesus monkeys (Macaca mulatta) ranging in age from 4-27 years. About half this sample comprised an experimental group subjected to 30% calorie restriction for six to seven years compared to the control group fed the same nutritionally fortified diet to approximate ad lib levels. Variables that met the following criteria were selected: (1) longitudinal change within the cohorts of control monkeys; (2) cross-sectional correlation with age across the adult lifespan in the control group; (3) stability of individual differences within all groups; and (4) no obvious redundancy with other selected variables. Five variables emerged from this step-wise selection, including the percentage lymphocytes, and serum levels of alkaline phosphatase, albumin, creatinine, and calcium. These variables were then submitted to a principal component analysis, which yielded a single component accounting for about 58% of the total variance. Based on this marked degree of covariance, these candidate biomarkers of aging could be combined into a biological age score (BAS) for the control and experimental groups. When chronological age was regressed onto BAS, the slopes of the control and experimental groups could be compared. Although a trend toward a slower aging rate in calorie-restricted monkeys was apparent, this analysis did not detect a statistically significant difference in the rate of aging between these groups estimated by this index. Despite this result, a logical strategy was confirmed for expanding the search for candidate biomarkers of aging to apply to this and to other studies assessing interventions that purport to affect the rate of aging in long-lived species.     

Gastrulation initiation in Caenorhabditis elegans requires the function of gad-1, which encodes a protein with WD repeats

Although the role of dopamine dysfunction is well established in Parkinson's disease, the effect of nigrostriatal degeneration on motor performance during normal aging is less well understood. In this study, aged rhesus monkeys (25-27 years old) displayed significant impairments relative to young (3-5 years old) cohorts in motor function as assessed on a fine motor task and home cage activity. Additionally, the clinical motor function of aged monkeys was impaired relative to young monkeys as assessed on a clinical rating scale. Unbiased stereologic measurements of the substantia nigra revealed a significant age-related loss of tyrosine hydroxylase-immunoreactive (TH-ir; 50.3%) and dopamine transporter-immunoreactive (DAT-ir; 33.2%) nigral neurons. The monkeys performance on the fine motor task and on the clinical rating scale was correlated with TH-ir neuronal counts. The number of DAT-ir nigral neurons was correlated with activity and clinical rating scale scores. Our results suggest that age-related motor impairments in nonhuman primates are associated with spontaneous decreases in TH-ir and DAT-ir nigral cells. The correlation of motor deficits with the loss of TH-ir and DAT-ir nigral neurons suggests that aged nonhuman primates may provide a useful model for mimicking changes seen in human aging and early Parkinson's disease.     

Molecular weight-dependent effects of hyaluronate on the arthritic synovium

Twenty-six rhesus monkeys were tested repeatedly at 4, 8, and 12 months of age to characterize the expression and development of their defensive responses induced by separation from their mothers and exposure to a potential threat. Results demonstrated that by 4 months of age infant monkeys engaged in adult-like context-dependent responses and adaptively regulated these responses in relation to the changing context. When separated from their mothers and alone, infants at 4 months of age were active and emitted frequent coo vocalizations. However, when exposed to the profile of a human face, infants responded by becoming behaviorally inhibited and freezing. At 8 months of age, a dramatic reduction in infants' separation-induced coos was observed, whereas their duration of threat-induced freezing remained unchanged. At 12 months of age, a further decrease in cooing occurred, while freezing duration was maintained. No sex differences were found in the expression of these behaviors or their developmental patterns. Individual differences in separation-induced cooing and threat-induced freezing were apparent and remained stable over the three ages studied. However, within animals no relation was found between individual differences in cooing and freezing. These data demonstrate important differences in the developmental patterns for the expression of cooing and freezing over the first year of life. Marked individual differences in separation-induced cooing and threat-induced freezing were apparent and remained stable from 4-12 months of age. The data support the hypothesis that these different defensive responses reflect different adaptive responses that likely have different underlying mechanisms. The similarities between these defensive responses in rhesus monkeys and humans suggests that understanding the factors that promote the development of individual differences in monkeys will illuminate important factors that promote individual differences in humans.     

The development of stereoacuity in infant rhesus monkeys

The emergence of stereopsis at 3-4 months postnatal in human infants is striking and has led to speculation that its rapid onset and subsequent development must be due to a dramatic reorganization of the brain. Stereopsis has never been measured in infant monkeys, but previous studies have demonstrated that many other visual functions develop four times faster in infant monkeys than in humans. We made longitudinal assessments of stereoacuity in 11 infant rhesus monkeys. A forced-choice preferential-looking technique was used to present random-dot stereograms during testing. By 8 weeks after birth, all of the monkeys were responding to at least coarse levels of disparity (1760" [seconds]), and by 13 weeks of age, all were responding to the relatively fine level of 88" disparity. Age of onset for stereopsis in monkeys was at about one-quarter the age when it occurs in humans, as expected. However, subsequent development proceeded at a similar absolute rate in monkeys and humans. The findings are discussed relative to the neural mechanisms which might be responsible for the differing rates of development.     

Aging in rhesus monkeys: Different windows on behavioral continuity and change.

Rhesus monkeys were observed longitudinally from 6 to 20 years of age, the period encompassing early to late adulthood in this species. Repeated-measures analyses of the monkeys' behavioral repertoire revealed 3 quite different pictures of the aging process. First, there were significant systematic changes in the levels of many categories of behavior with increasing age, although the direction and timing of change varied from category to category. Second, for most categories, individual differences among the monkeys were highly stable from early to late adulthood. Finally, there was remarkable consistency within individual behavioral profiles across the entire study such that each monkey retained its distinctive behavioral features (personality) throughout its adult years. Thus, aging in rhesus monkeys is characterized by both continuity and change. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Potentially predictive and manipulable blood serum correlates of aging in the healthy human male: progressive decreases in bioavailable testosterone, dehydroepiandrosterone sulfate, and the ratio of insulin-like growth factor 1 to growth hormone

A cross-sectional survey was made in 56 exceptionally healthy males, ranging in age from 20 to 84 years. Measurements were made of selected steroidal components and peptidic hormones in blood serum, and cognitive and physical tests were performed. Of those blood serum variables that gave highly significant negative correlations with age (r > -0.6), bioavailable testosterone (BT), dehydroepiandrosterone sulfate (DHEAS), and the ratio of insulin-like growth factor 1 (IGF-1) to growth hormone (GH) showed a stepwise pattern of age-related changes most closely resembling those of the age steps themselves. Of these, BT correlated best with significantly age-correlated cognitive and physical measures. Because DHEAS correlated well with BT and considerably less well than BT with the cognitive and physical measures, it seems likely that BT and/or substances to which BT gives rise in tissues play a more direct role in whatever processes are rate-limiting in the functions measured and that DHEAS relates more indirectly to these functions. The high correlation of IGF-1/GH with age, its relatively low correlation with BT, and the patterns of correlations of IGF-1/GH and BT with significantly age-correlated cognitive and physical measures suggest that the GH-IGF-1 axis and BT play independent roles in affecting these functions. Serial determinations made after oral ingestion of pregnenolone and data from the literature suggest there is interdependence of steroid metabolic systems with those operational in control of interrelations in the GH-IGF-1 axis. Longitudinal concurrent measurements of serum levels of BT, DHEAS, and IGF-1/GH together with detailed studies of their correlations with age-correlated functional measures may be useful in detecting early age-related dysregulations and may be helpful in devising ameliorative approaches.     

Acquisition of the classically conditioned eyeblink response in humans over the life span.

Human subjects ranging in age from 18 to 85 years underwent classical conditioning of the eyeblink response to a tone conditioned stimulus (CS) and an air-puff unconditioned stimulus (UCS). There was a decline in percentage of conditioned responses with age. This decline was most noticeable in subjects over age 50. These conditioning deficits were not due to age-related changes in sensitivity to the tone CS or the air-puff UCS, nor could the conditioning deficits be attributed to an age-related decline in general cognitive abilities or to changes in spontaneous blink rates. The results are discussed in terms of using the classically conditioned eyeblink in humans in conjunction with the classically conditioned nictitating membrane response in rabbits as a model system for studying the neurobiology of age-related conditioning deficits. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Widespread unilateral increased rib uptake on bone scan

Some neuropathological changes characteristic of aging and Alzheimer's disease (AD) in humans are present also in senescent non-human primates. The human apoE4 allele is associated with an increased risk of developing late-onset familial and sporadic AD. We found that rhesus monkeys and three subspecies of squirrel monkeys are homozygous for apoE phenotype with arginine at positions 112 and 158 as in human apoE4. However, in both species threonine replaces arginine at position 61 of human apoE. It was previously shown that arginine 61 was critical in determining apoE4 lipoprotein distribution in humans.     

Adult-onset energy restriction of rhesus monkeys attenuates oxidative stress-induced cytokine expression by peripheral blood mononuclear cells

We previously reported that energy restriction (ER) of mice attenuated age-associated increases in serum levels of interleukin-6 (IL-6). Here, we studied peripheral blood mononuclear cells (PBMC) from male rhesus monkeys to investigate the following: 1) the production of IL-6 and other cytokines become dysregulated with aging; 2) ER influences cytokine production and mRNA expression; and, 3) oxidative stress, as induced in vitro by xanthine and xanthine oxidase (X/XOD), influences cytokine mRNA and protein levels. Two types of comparisons were made as follows: 1) between normally fed young (6-9 y) and old monkeys (22-33 y); and 2) between middle-aged monkeys (15-21 y) fed either a normal energy intake or subjected to ER (for 5.5 y at 30% less than base-line intake). IL-6 protein levels and X/XOD-induced IL-6 mRNA levels in PBMC from old monkeys were significantly greater than those in PBMC from young animals. In contrast, interleukin-1beta (IL-1beta) and interleukin-8 mRNA levels were not strongly influenced by advancing age. X/XOD, which increased levels of protein carbonyls (indicative of oxidative damage) in PBMC, induced the expression of all three cytokines. ER reduced IL-6 protein and mRNA levels induced by X/XOD and the unstimulated mRNA levels of IL-1beta. These results indicate that, in a nonhuman primate model, oxidative stress may contribute to age-associated increases in the levels of certain cytokines and that adult-onset ER partially ameliorates this alteration.     

Comparative assessment of psychomotor performance: target prediction by humans and macaques (Macaca mulatta)

Although nonhuman primates such as rhesus monkeys (Macaca mulatta) have been useful models of many aspects of cognition and performance, it has been argued that, unlike humans, they may lack the capacity to respond as predictor-operators. Data from the present series of experiments undermine this claim, suggesting instead a continuity of predictive competency between humans and nonhuman primates. A prediction coefficient was devised to examine the degree to which each subject's response path approximated the optimal predictive strategy. Whereas human subjects (N = 30) generally predicted more accurately, rhesus monkeys (N = 10) also significantly anticipated the movements of the target in all conditions. It appears that humans and rhesus monkeys both exhibit the capacity to respond to where a stimulus is going.     

Cognitive function in aged ovariectomized female rhesus monkeys.

To determine whether ovariectomy exacerbates age-related cognitive decline, the performance of 6 aged monkeys that had been ovariectomized early in life (OVX-Aged) was compared to that of 8 age-matched controls with intact ovaries (INT-Aged) and that of 5 young controls with intact ovaries (INT-Young) in tasks of visual recognition memory, object and spatial memory, and executive function. The OVX-Aged monkeys were marginally more impaired than the INT-Aged monkeys on the delayed nonmatching-to-sample with a 600-s delay. In contrast, they performed significantly better than the INT-Aged controls on the spatial condition of the delayed recognition span test. The hypothesis that prolonged estrogenic deprivation may exaggerate the age-related decline in visual recognition memory will require additional support. However, the findings suggest that long-term ovariectomy may protect against the development with aging of spatial memory deficits. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Determinants of functional status in healthy Italian nonagenarians and centenarians: a comprehensive functional assessment by the instruments of geriatric practice

OBJECTIVE: To evaluate the physical ability and psychocognitive status of a population more than 90 years of age with regard to sociodemographic, behavioral, and biomedical variables known to affect functional status in old age. DESIGN: A survey design was used. SETTING: Emilia Romagna, Northern Italy. PARTICIPANTS: Eighty-four healthy community-dwelling subjects aged 90 to 106 years. MEASUREMENTS: Sociodemographic variables, health behavior, anthropometric indices, and serum DHEAS levels were recorded. Functional assessment was performed by instruments currently used in geriatric practice: the Mini-Mental State Examination (MMSE), Geriatric Depression Scale (GDS), and Activities of Daily Living (ADL) scale. A stepwise multiple regression analysis was performed. RESULTS: GDS scores correlated directly with MMSE scores and inversely with ADL severity scores. Poor education, institutionalization, sensory impairment, muscular mass loss, and lower DHEAS levels were the variables with the highest correlation to functional impairment. Smoking, alcohol consumption, and marital status were relatively unimportant. An inverse association was found between DHEAS levels and dependency scores of single ADLs (continence, mobility). CONCLUSION: Impaired cognitive and physical ability with no increase in depression prevalence was found in a sample of subjects more than 90 years of age free of major age-related disease. Muscular mass and DHEAS levels seem to play a role in maintaining physical independence. In turn, physical independence, as well as social and cultural factors, strongly affect the compliance of long-lived subjects with psychocognitive tests currently used in the clinical evaluation of younger old people, suggesting that these instruments are not reliable for screening for cognitive impairment and depression in the oldest old subjects.     

A prospective study on cortisol, dehydroepiandrosterone sulfate, and cognitive function in the elderly

The objective of this study was to investigate the relation between the peripheral concentrations of the adrenal steroid hormones cortisol and dehydroepiandrosterone sulfate (DHEAS) and cognitive impairment and decline. A prospective study design was used. The setting was a suburb of Rotterdam, The Netherlands. The study population consisted of a sample of 189 healthy participants from the population-based Rotterdam Study, aged 55-80 yr, who were invited for an additional examination. Follow-up examinations took place 1.9 yr after baseline, on the average. We determined fasting blood levels of DHEAS before dexamethasone administration and of cortisol and corticosteroid-binding globulin before and after the administration of 1 mg dexamethasone overnight. The 30-point Mini-Mental State Examination (MMSE) was used to assess cognition. The associations with cognitive impairment (MMSE score of <26; 6% of the sample) and cognitive decline (drop in MMSE score of >1 point/yr; 24%) were estimated using logistic regression, with adjustment for age, sex, education, and depressive symptoms. An increase of 1 SD in the estimate of free cortisol (SD = 30.3) was associated with cognitive impairment, although not significantly [odds ratio (OR) = 1.5; 95% confidence interval (CI), 0.9-2.4]. A 1 SD increase in the natural logarithm of cortisol after the administration of 1 mg dexamethasone (SD = 0.68) was associated with an OR for cognitive decline of 1.5 (95% CI, 1.0-2.3). A 1 SD increase in DHEAS (SD = 2.10 micromol/L) was inversely, but nonsignificantly, related to cognitive impairment (OR = 0.5; 95% CI, 0.2-1.1) and cognitive decline (OR = 0.6; 95% CI, 0.4-1.1). The ratio of free cortisol over DHEAS was significantly related to cognitive impairment (OR = 1.8; 95% CI, 1.0-3.2). This prospective study among healthy elderly subjects suggested that basal free cortisol levels were positively related to cognitive impairment, and cortisol levels after dexamethasone treatment were related to cognitive decline. There was an inverse, but nonsignificant, association between DHEAS and cognitive impairment and decline.     

Impairment of long-term associative memory in aging snails (Lymnaea stagnalis).

Age-dependent impairment in learning and memory functions occurs in many animal species, including humans. Although cell death contributes to age-related cognitive impairment in pathological forms of aging, learning and memory deficiencies develop with age even without substantial cell death. The molecular and cellular basis of this biological aging process is not well understood but seems to involve a decline in the aging brain's capacity for experience-dependent plasticity. To aid in resolving this issue, we used a simple snail appetitive classical conditioning paradigm in which the underlying molecular, cellular, and neural network functions can be directly linked to age-associated learning and memory performance (i.e., the Lymnaea stagnalis feeding system). Our results indicate that age does not affect the acquisition of appetitive memory but that retention and/or consolidation of long-term memory become progressively impaired with advancing age. The latter phenomenon correlates with declining electrophysiological excitability in key neurons controlling the feeding behavior. Together, these results present the Lymnaea feeding system as a powerful paradigm for investigations of cellular and molecular foundations of biological aging in the brain. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Does growth hormone prevent or accelerate aging?

It is very well documented that plasma growth hormone (GH) levels decline with age in the human and in experimental animals, and there is considerable evidence that age-related changes in body composition may be caused by reduced function of the GH-IGF-I system. However, excessive GH levels are associated with reduced life expectancy in acromegalic patients and with symptoms of accelerated aging in GH transgenic mice. Hereditary dwarf mice deficient in GH, prolactin, and TSH live much longer than their normal siblings. Possible mechanisms of delayed aging in dwarf mice include lower core body temperature and reduced oxidative processes. It is suggested that the controversies concerning the apparent potential of GH to both prevent and accelerate aging may be reconciled by interpreting the results in light of the negative relationship between body size and life span within a species.     

Cold-induced thermoregulation and biological aging

Aging is associated with diminished cold-induced thermoregulation (CIT). The mechanisms accounting for this phenomenon have yet to be clearly elucidated but most likely reflect a combination of increased heat loss and decreased metabolic heat production. The inability of the aged subject to reduce heat loss during cold exposure is associated with diminished reactive tone of the cutaneous vasculature and, to a lesser degree, alterations in the insulative properties of body fat. Cold-induced metabolic heat production via skeletal muscle shivering thermogenesis and brown adipose tissue nonshivering thermogenesis appears to decline with age. Few investigations have directly linked diminished skeletal muscle shivering thermogenesis with the age-related reduction in cold-induced thermoregulatory capacity. Rather, age-related declines in skeletal muscle mass and metabolic activity are cited as evidence for decreased heat production via shivering. Reduced mass, GDP binding to brown fat mitochondria, and uncoupling protein (UCP) levels are cited as evidence for attenuated brown adipose tissue cold-induced nonshivering thermogenic capacity during aging. The age-related reduction in brown fat nonshivering thermogenic capacity most likely reflects altered cellular signal transduction rather than changes in neural and hormonal signaling. The discussion in this review focuses on how alterations in CIT during the life span may offer insight into possible mechanisms of biological aging. Although the preponderance of evidence presented here demonstrates that CIT declines with chronological time, the mechanism reflecting this attenuated function remains to be elucidated. The inability to draw definitive conclusions regarding biological aging and CIT reflects the lack of a clear definition of aging. It is unlikely that the mechanisms accounting for the decline in cold-induced thermoregulation during aging will be determined until biological aging is more precisely defined.