Age-related alterations of plasma glutathione and oxidation of redox potentials in chimpanzee (Pan troglodytes) and rhesus monkey (Macaca mulatta).

Chimpanzee (Pan troglodytes) and rhesus macaque (Macaca mulatta) and humans (Homo sapiens) share physiological and genetic characteristics, but have remarkably different life spans, with chimpanzees living 50-60 % and the rhesus living 35-40 % of maximum human survival. Since oxidative processes are associated with aging and longevity, we might expect to see species differences in age-related oxidative processes. Blood and extracellular fluid contain two major thiol redox nodes, glutathione (GSH)/glutathione-disulfide (GSSG) and cysteine (Cys)/cystine (CySS), which are subject to reversible oxidation-reduction reactions and are maintained in a dynamic non-equilibrium state. Disruption of these thiol redox nodes leads to oxidation of their redox potentials (EhGSSG and EhCySS) which affects cellular physiology and is associated with aging and the development of chronic diseases in humans. The purpose of this study was to measure age-related changes in these redox thiols and their corresponding redox potentials (Eh) in chimpanzees and rhesus monkeys. Our results show similar age-related decreases in the concentration of plasma GSH and Total GSH as well as oxidation of the EhGSSG in male and female chimpanzees. Female chimpanzees and female rhesus monkeys also were similar in several outcome measures. For example, similar age-related decreases in the concentration of plasma GSH and Total GSH, as well as age-related oxidation of the EhGSSG were observed. The data collected from chimpanzees and rhesus monkeys corroborates previous reports on oxidative changes in humans and confirms their value as a comparative reference for primate aging.

Autonomic substrates of the response to pups in male prairie voles.

Caregiving by nonparents (alloparenting) and fathers is a defining aspect of human social behavior, yet this phenomenon is rare among mammals. Male prairie voles (Microtus ochrogaster) spontaneously exhibit high levels of alloparental care, even in the absence of reproductive experience. In previous studies, exposure to a pup was selectively associated with increased activity in oxytocin and vasopressin neurons along with decreased plasma corticosterone. In the present study, physiological, pharmacological and neuroanatomical methods were used to explore the autonomic and behavioral consequences of exposing male prairie voles to a pup. Reproductively naïve, adult male prairie voles were implanted with radiotransmitters used for recording ECG, temperature and activity. Males responded with a sustained increase in heart-rate during pup exposure. This prolonged increase in heart rate was not explained by novelty, locomotion or thermoregulation. Although heart rate was elevated during pup exposure, respiratory sinus arrhythmia (RSA) did not differ between these males and males exposed to control stimuli indicating that vagal inhibition of the heart was maintained. Blockade of beta-adrenergic receptors with atenolol abolished the pup-induced heart rate increase, implicating sympathetic activity in the pup-induced increase in heart rate. Blockade of vagal input to the heart delayed the males' approach to the pup. Increased activity in brainstem autonomic regulatory nuclei was also observed in males exposed to pups. Together, these findings suggest that exposure to a pup activates both vagal and sympathetic systems. This unique physiological state (i.e. increased sympathetic excitation of the heart, while maintaining some vagal cardiac tone) associated with male caregiving behavior may allow males to both nurture and protect infants.

Menopause occurs late in life in the captive chimpanzee (Pan troglodytes).

Menopause in women occurs at mid-life. Chimpanzees, in contrast, continue to display cycles of menstrual bleeding and genital swelling, suggestive of ovulation, until near their maximum life span of about 60 years. Because ovulation was not confirmed hormonally, however, the age at which chimpanzees experience menopause has remained uncertain. In the present study, we provide hormonal data from urine samples collected from 30 female chimpanzees, of which 9 were old (>30 years), including 2 above the age of 50 years. Eight old chimpanzees showed clear endocrine evidence of ovulation, as well as cycles of genital swelling that correlated closely with measured endocrine changes. Endocrine evidence thus confirms prior observations (cyclic anogenital swelling) that menopause is a late-life event in the chimpanzee. We also unexpectedly discovered an idiopathic anovulation in some young and middle-aged chimpanzees; this merits further study. Because our results on old chimpanzees validate the use of anogenital swelling as a surrogate index of ovulation, we were able to combine data on swelling and urinary hormones to provide the first estimates of age-specific rates of menopause in chimpanzees. We conclude that menopause occurs near 50 years of age in chimpanzees as it does in women. Our finding identifies a basic difference between the human and chimpanzee aging processes: female chimpanzees can remain reproductively viable for a greater proportion of their life span than women. Thus, while menopause marks the end of the chimpanzee's life span, women may thrive for decades more.

Social isolation modulates corticotropin-releasing factor type 2 receptor, urocortin 1 and urocortin 2 mRNAs expression in the cardiovascular system of prairie voles.

The purpose of the present study was to examine the effect of social isolation stress on the expression of messengers ribonucleic acid (mRNAs) for corticotropin-releasing factor receptor type 2 (CRF2 receptor), urocortin 1 (Ucn 1) and urocortin 2 (Ucn 2) in the cardiovascular system of female and male prairie voles (Microtus ochrogaster). Isolation for 1 h (single isolation) or 1 h of isolation every day for 4 weeks (repeated isolation) was followed by a marked increase in plasma corticosterone level. However, continuous isolation for 4 weeks (chronic isolation) did not significantly affect plasma corticosterone level in female or male animals. A single period of isolation did not influence the expression of the CRF2 receptor, however, both repeated and chronic isolation significantly decreased CRF2 receptor mRNA in the ventricle and aorta of both sexes. Neither single nor chronic isolation significantly affected Ucn 1 mRNAs expression; however, repeated isolation increased Ucn 1 mRNA expression in the ventricles of female and male animals. Although, a single isolation produced no effect on cardiac Ucn 2 mRNA expression, both repeated and chronic isolation were followed by increased heart Ucn 2 mRNA expression in both sexes. We speculate that during repeated isolation Ucn 1 along with Ucn 2 are increased, which in turn down-regulates CRF2 receptor mRNA expression, and that Ucn 2 also may be one of factors responsible for the down-regulation of CRF2 receptor mRNA expression in cardiovascular system that is associated with chronic isolation.

Stress differentially modulates mRNA expression for corticotrophin-releasing hormone receptors in hypothalamus, hippocampus and pituitary of prairie voles.

This study compares the effect of an acute stressor (restraint for 1h) versus a chronic stressor (social isolation for 4 weeks) on the expression of mRNAs for corticotropin-releasing hormone (CRH), CRH receptor type 1 (CRH-R1) and type 2 (CRH-R2) in the hypothalamus, hippocampus and pituitary of socially monogamous female prairie voles (Microtus ochrogaster). Animals were studied immediately following a stressor or as a function of repairing with a familiar sibling. Despite elevated expression of CRH mRNA, no alteration of CRH-R1 mRNA in the hypothalamus was observed following restraint stress or 4 weeks of social isolation. Hypothalamic CRH-R2 mRNA was significantly lower in voles exposed to restraint or isolation. CRH-R2 mRNA also remained down-regulated in isolated animals when these animals were re-paired with their sibling for one day following 28 days of isolation. Restraint, but not isolation, significantly increased CRH-R1 mRNA and decreased CRH-R2 mRNA in the pituitary. However, these differences were no longer observed when these animals were re-paired with their sibling for one day. Despite elevated CRH mRNA expression, CRH-R1 mRNA did not increase in the hippocampus following restraint or social isolation. Social isolation, but not restraint stress, increased CRH-R2 mRNA in the hippocampus, when these animals were re-paired with their sibling for one day the modulation of CRH mRNA remained up-regulated. Plasma corticosterone was elevated only following restraint, and not in animals that were handled, isolated or re-paired. The results of the present study reveal that acute restraint as well as social isolation can have significant consequences for the modulation of gene expression for the CRH receptors in brain and pituitary of prairie voles.

The effect of social environment on markers of vascular oxidative stress and inflammation in the Watanabe heritable hyperlipidemic rabbit.

OBJECTIVE: Previous research demonstrated that social environment can influence progression of atherosclerosis in the Watanabe Heritable Hyperlipidemic (WHHL) rabbit. This study examined the effect of social environment on markers of oxidative stress and inflammation to clarify the physiological pathways potentially responsible for the influence of social environment on disease. METHODS AND RESULTS: WHHL rabbits were assigned to 1 of 3 social groups: an unstable group, in which unfamiliar rabbits were paired daily, with the pairing switched each week; a stable group, in which littermates were paired daily; and an individually-caged group. The stable group engaged in more affiliative social behavior than the unstable group. The unstable group showed more agonistic behavior compared with the stable group and higher C-reactive protein levels than the individually caged group. The individually caged group was behaviorally sedentary, had higher 24-hour urinary catecholamine levels than the other groups, and exhibited higher NAD(P)H-oxidase activity in the aortic arch relative to the stable group. CONCLUSIONS: The results suggest that social environment creates distinct behavioral contexts that can affect markers of inflammation and oxidative stress early in the development of atherosclerosis. Specifically, physical inactivity associated with individual caging affects indices of oxidative stress and inflammation. These pathophysiological markers may help to explain behaviorally related differences in the extent of atherosclerosis observed in prior studies.

Social experience influences hypothalamic oxytocin in the WHHL rabbit.

Social experience influences behavior and the progression of atherosclerosis in the Watanabe Heritable Hyperlipidemic (WHHL) rabbit, such that WHHL rabbits exposed to a consistent, stable social experience exhibited more affiliative social behavior and less aortic atherosclerosis compared to other social groups. Oxytocin (OT) has been implicated in the expression of social behavior, stress responses, and may provide a mechanism by which social experience influences atherogenesis in WHHL rabbits. The current study examined acute and chronic changes in central and peripheral OT before and after WHHL rabbits were exposed to one of three social conditions. Cannula implanted adjacent to the hypothalamic paraventricular nucleus (PVN) allowed chronic sampling of extracellular OT concentration via microdialysis. Rabbits were exposed to one of three social conditions: an Unstable group, with initially unfamiliar rabbits paired daily for 4h during the initial week and similarly paired with a different, unfamiliar rabbit each week; a Stable group; with the same 2 littermates paired daily for 4h the entire study; and an Individually Caged group. Dialysates from the PVN and blood from the marginal ear vein were collected twice, 20 days apart, from rabbits before and after 2h of exposure to their respective social condition. Dialysates were assayed for OT and plasma was assayed for OT, catecholamines and glucocorticoids. There were no changes in PVN OT in any group following the initial social experience. In contrast, after 20 consecutive days of exposure to their respective social condition, PVN OT increased significantly in the Unstable group, but was relatively unchanged in the Stable group following the social experience on day 22. Peripheral OT was not altered in any group following the 2h social experience on day 1 or 22. The concentration of peripheral OT was the highest in the Stable group at all times. The Stable group also exhibited significantly less aortic atherosclerosis, consistent with earlier findings from our laboratory. Data from the present study suggest that the type of social experience WHHL rabbits are exposed influences PVN OT, social behavior and the progression of atherosclerosis in the WHHL rabbit model of disease.

Effect of behavioral interventions on insulin sensitivity and atherosclerosis in the Watanabe heritable hyperlipidemic rabbit.

OBJECTIVE: A previous study suggested that insulin metabolic variables play a role in the progression of atherosclerosis in Watanabe heritable hyperlipidemic (WHHL) rabbits. The present study sought to determine: 1) if young, individually caged WHHLs are insulin-resistant relative to New Zealand white (NZW) rabbits and 2) whether dietary or exercise interventions can improve insulin sensitivity and slow the development of atherosclerosis in these animals. METHODS: Forty-two WHHLs were assigned to a dietary, exercise, or control condition, and 12 NZWs were used as a comparison control group. The intervention ran from 3 to 7 months of age, and all animals received an intravenous glucose tolerance test at the beginning and end of the intervention. RESULTS: WHHLs were insulin-resistant relative to NZWs at 3 months of age. Whereas the dietary intervention was effective in controlling insulin resistance, WHHLs in the exercise group without dietary restriction and the control group exhibited significant increases in insulin resistance. No intervention significantly influenced the progression of atherosclerosis. CONCLUSIONS: Young WHHLs are insulin-resistant during an early period when atherosclerosis is developing rapidly. Dietary restriction, but not exercise without weight control, is effective in controlling insulin metabolic variables in the WHHL model. Although dietary intervention can reduce cardiovascular risk factors such as insulin resistance, it is not effective in slowing the development of atherosclerosis in these genetically dyslipidemic animals. Similarly, exercise training, without dietary control, does not influence the progression of disease in WHHLs.