Social behavior and gender in biomedical investigations using monkeys: studies in atherogenesis.

We review the use of socially housed cynomolgus monkeys (Macaca fascicularis) in biomedical research with emphasis on studies of atherosclerosis, particularly in the two specific domains of atherosclerosis investigation for which nonhuman primates are especially well-suited as animal models: gender differences and psychosocial influences. We found that the presence of normal ovarian function prevented exacerbation of diet-induced coronary artery atherosclerosis in female monkeys. However, any manipulation or condition which impaired ovarian function tended to diminish or abolish this "female" protection. Among group-housed female monkeys, low social status was accompanied by ovarian dysfunction and, not surprisingly, by exacerbated coronary artery atherosclerosis as well. Surgical menopause (ovariectomy) also induced exacerbation of coronary atherosclerosis in monkeys, a situation which was prevented by estrogen replacement therapy. Conversely, pregnancy (a hyperestrogenic state) resulted in markedly diminished atherosclerosis. A somewhat different pattern of atherogenesis emerged among socially-housed males. Here, socially dominant animals developed exacerbated coronary artery atherosclerosis, but only under conditions of social stress (viz., disruption caused by periodic reorganization of social group membership). We hypothesized that exposure to repeated group reorganizations provoked activation of the sympathetic nervous system among dominant animals; in turn, the hemodynamic and metabolic concomitants of sympathetic activation may have damaged the coronary arteries of these monkeys, potentiating atherogenesis. To test this hypothesis, males were housed in unstable social groupings, with half of the monkeys administered a beta-adrenergic blocking agent (to attenuate heart rate and blood pressure responses to stress). The beta-blocker inhibited atherosclerosis, but only among those animals behaviorally predisposed to develop exacerbated lesions (i.e. dominant monkeys). These results support the view that monkeys are suitable research models of atherosclerosis, a disease that affects millions of humans.     

Cognition, mood disorders, and sex hormones

Macaques (Macaca spp.) are useful models to evaluate effects of ovarian sex steroids and selective estrogen receptor modulators (SERMs) on mood and cognitive function due to similarities to women in their reproductive and central nervous systems. The results of nonhuman primate studies support the hypothesis that estrogen mediates specific aspects of attention and memory, yet much work is needed to understand which cognitive processes are affected, whether natural versus surgical menopause effects are different, and the interaction of age and ovarian senescence on cognitive function. This knowledge is necessary to determine whether to support the cognitive function of women in the menopausal phase of life and, if so, to determine efficacious therapeutic interventions. Mood disorders are prevalent in women and are associated with reproductive function in women and macaques. Exogenous steroid therapies, including oral contraceptives and postmenopausal hormone replacement therapies, have behavioral effects in women and appear to affect the behavior and underlying neural substrates of monkeys. Additional research is necessary to confirm and extend these observations. Ovarian steroids have multiple effects on serotonin synthesis, reuptake, and degradation, on neural activity that drives serotonin release, and on receptor activation in primates. This system modulates cognitive function and mood and is the target of a broad class of antidepressant therapies. Understanding the effects of ovarian steroids on the neural serotonergic system is necessary to understand depression in women. These studies are best carried out in primate models, which are more similar to humans in neural serotonergic function than other animal models.     

Postpartum depression: Etiology,treatment and consequences for maternal care

This article is part of a Special Issue “Parental Care”. Pregnancy and postpartum are associated with dramatic alterations in steroid and peptide hormones which alter the mothers' hypothalamic pituitary adrenal (HPA) and hypothalamic pituitary gonadal (HPG) axes. Dysregulations in these endocrine axes are related to mood disorders and as such it should not come as a major surprise that pregnancy and the postpartum period can have profound effects on maternal mood. Indeed, pregnancy and postpartum are associated with an increased risk for developing depressive symptoms in women. Postpartum depression affects approximately 10–15% of women and impairs mother–infant interactions that in turn are important for child development. Maternal attachment, sensitivity and parenting style are essential for a healthy maturation of an infant's social, cognitive and behavioral skills and depressed mothers often display less attachment, sensitivity and more harsh or disrupted parenting behaviors, which may contribute to reports of adverse child outcomes in children of depressed mothers. Here we review, in honor of the “father of motherhood”, Jay Rosenblatt, the literature on postnatal depression in the mother and its effect on mother–infant interactions. We will cover clinical and pre-clinical findings highlighting putative neurobiological mechanisms underlying postpartum depression and how they relate to maternal behaviors and infant outcome. We also review animal models that investigate the neurobiology of maternal mood and disrupted maternal care. In particular, we discuss the implications of endogenous and exogenous manipulations of glucocorticoids on maternal care and mood. Lastly we discuss interventions during gestation and postpartum that may improve maternal symptoms and behavior and thus may alter developmental outcome of the offspring.     

A review of sexual initiating behavior by male and female cynomolgus monkeys and some species comparisons

The sexual initiating behavior of male and female cynomolgus monkeys (Macaca fascicularis) observed during standard laboratory tests is reviewed and compared with that of rhesus monkeys (M. mulatta) observed under identical conditions. Species differences in sexual behavior are related here to differences in habitat, sexual dimorphism, and the dominance gradient between the sexes. Compared with rhesus monkeys, cynomolgus monkeys appear to be more arboreal, less sexually dimorphic, and have a smaller dominance gradient between the sexes. They exhibit a facultative single-mount copulatory pattern rather than the serial mount pattern of the rhesus monkey. Female cynomolgus monkeys are less dominated than rhesus females by their male partners. Direct aggression between mates is more frequent and redirected aggression occurs less often than in rhesus monkeys. These behavioral differences affect the interpretation of changes in initiation rates that occur (1) during the menstrual cycle, (2) when females are ovariectomized and given hormone replacement treatments, and (3) when males are castrated and treated with androgens. We conclude that estradiol in the female and testosterone in the male increase the sexual motivation of both the treated and the untreated partner. Valid interpretations of changes in initiation rates depend on accurate and exclusive definitions of behavior and on a consideration of the behavioral context in which they are made.     

Masochistic Dreams: A Gender-Related Diathesis for Depression Revisited

Masochistic dreams, as defined by Beck (1967), are reportedly more prevalent among women and individuals with past or present depression. However, it is unclear whether these prevalence differences are a function of depressogenic personality traits or fluctuating mood symptoms. In the present study, 30 men and 30 women without histories of major depression slept two consecutive nights in a sleep laboratory and reported their dreams from each REM period on the second night. Dream content from this sample was compared to that of 60 depressed participants who were studied previously under the same protocol. Analyses did not support a heightened prevalence of masochistic dreams among women or depressed individuals. Interestingly, the masochistic dreams of the non-depressed sample were equally distributed across the night, whereas depressed individuals tend to report masochistic dreams closer to morning. This hypothesized pattern suggests that masochistic dreams may be pathognomic of depression in that their occurrence near the end of the night affects morning mood with negative dream residue.     

Usefulness of the monkey model to investigate the role soy in postmenopausal women's health

Some of the important health issues for postmenopausal women include cardiovascular disease, osteoporosis, breast cancer, and relief of menopausal symptoms. Ovariectomized cynomolgus monkeys (Macaca fascicularis) have many strengths as models for research in this area including a close phylogenetic relationship to humans, similarities in lipid/lipoprotein metabolism and coronary artery anatomy, similar skeletal anatomical and morphological characteristics, mammary glands with similar pathophysiological characteristics, and a 28-day menstrual cycle with similar hormonal fluctuations. Monkeys (macaques) also experience declining ovarian function and irregular menstrual cycles (natural menopause) when they approach 24 to 29 yr of age. However, because of their very short life span after natural menopause, ovariectomized macaques are used to model postmenopausal women. The cynomolgus monkey model has been useful in defining the potential cardiovascular benefits of soy foods and soy supplements; however, it remains unclear whether the observations are generalizable to all women or only to those who, like cynomolgus monkeys, convert the soy isoflavone daidzein to the metabolite equol. Particularly important has been the use of the cynomolgus monkey model to understand the effects of soy on breast health. There is evidence from a cynomolgus monkey trial to suggest that soy/soy phytoestrogens have no estrogen agonist effects for breast. Finally, soy/soy phytoestrogens do not appear to be an adequate alternative to postmenopausal hormone therapy. Nevertheless, important attributes of soy have been identified, and it may have potential as a complementary component to hormone therapy.     

Genetic substructure in cynomolgus macaques (Macaca fascicularis) on the island of Mauritius

Background

Nonhuman primates are commonly used in biomedical research as animal models of human disease and behavior. Compared to common rodent models, nonhuman primates are genetically, physiologically, behaviorally and neurologically more similar to humans owing to more recent shared ancestry and therefore provide the advantage of greater translational validity in preclinical studies. The cynomolgus macaque (Macaca fascicularis) is one of the most commonly used nonhuman primates in academic and industry settings, yet population genetic research has revealed significant substructure throughout the species distribution that may confound studies. Cynomolgus monkeys introduced to Mauritius specifically have previously been thought to maintain the least genetic heterogeneity of all cynomolgus monkeys, although recent work, including work from our lab, suggests macaques from Mauritius too may harbor cryptic substructure.

Results

To evaluate putative substructure in Mauritian cynomolgus macaques, we designed a panel of 96 single nucleotide polymorphisms based on preliminary findings from previous work to screen 246 of cynomolgus monkeys from two primary suppliers. Results from this study support substructure in Mauritian macaques and suggest a minimum of two populations and maybe three on Mauritius, with moderate admixture.

Conclusion

These findings inform the natural history of these monkeys suggesting either a previously unrecognized physical or ecological barrier to gene flow on Mauritius and/or the breakdown of historic substructure resulting from the history of macaque introduction to the island. These findings are relevant to ongoing research using these models in part because of increased appreciation of segregating common variation with functional effects and may be used to better inform animal selection in preclinical research.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2164-15-748) contains supplementary material, which is available to authorized users.     

Experimental induction of reduced ovarian reserve in a nonhuman primate model (Macaca fascicularis)

Chronic diseases including coronary heart disease and osteoporosis represent a substantial health burden to postmenopausal women, yet the initiation of these conditions and their relationships with reproductive aging remain poorly understood. This situation is due, in part, to the lack of animal models reflecting ovarian and hormonal characteristics of peri- and postmenopausal women. Ovaries of women approaching menopause are nearly depleted of primordial follicles but retain a pool of larger developing follicles and androgen-producing stroma, a condition known as reduced ovarian reserve (ROR). The long-term goal of the research presented here was to create a monkey model of reproductive aging, beginning with ROR and progressing to perimenopause and finally postmenopause. Here we sought to develop a method to reduce primordial follicles in cynomolgus monkeys (Macaca fascicularis) and document hormonal changes associated with follicle reduction or ROR. At 30 d after surgical placement of a biodegradable fiber containing approximately 200 mg of 4-vinlycyclohexene diepoxide (VCD) next to one ovary in each of 8 monkeys, primordial follicles were reduced by approximately 70%, with a corresponding decrease (83%) in antimüllerian hormone (AMH, a serum marker of ovarian follicle numbers). At 4 mo after VCD-treatment of both ovaries in 29 monkeys (approximately 200 mg VCD per ovary), AMH was reduced 56% from baseline, testosterone was unchanged, and follicular phase estradiol was slightly increased. These data indicate that VCD treatment markedly reduced primordial follicles while preserving larger estradiol- and testosterone-producing follicles and ovarian stroma, a condition that mimics ROR in women.     

The Effect of Antenatal Depression and Selective Serotonin Reuptake Inhibitor Treatment on Nerve Growth Factor Signaling in Human Placenta

Depressive symptoms during pregnancy are common and may have impact on the developing child. Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed antidepressant treatment, but unfortunately, these treatments can also negatively affect the behavioral development and health of a child during pregnancy. In addition, serotonin (5-HT) exerts neurotrophic actions with thus far not fully known effects in the offspring. The neurotrophic growth factor (NGF) is involved in neuronal cell survival and differentiation, and altered placenta levels have been found to increase the risk for pregnancy complications, similar to those found in women treated with SSRIs. We therefore investigated whether the NGF signaling pathway was altered in the placenta from women treated with SSRIs (n = 12) and compared them with placenta from depressed (n = 12) and healthy mothers (n = 12). Results from immunohistochemical stainings revealed that placental NGF protein levels of SSRI-treated women were increased in both trophoblasts and endothelial cells compared with depressed and control women. In addition, downstream of the NGF receptor TrkA, increased levels of the signaling proteins ROCK2 and phosphorylated Raf-1 were found in stromal cells and a tendency towards increased levels of ROCK2 in trophoblasts and endothelial cells in SSRI-treated women when compared to healthy controls. SSRI-treated women also displayed increased levels of phosphorylated ROCK2 in all placental cell types studied in comparison with depressed and control women. Interestingly, in placental endothelial cells from depressed women, NGF levels were significantly lower compared to control women, but ROCK2 levels were increased compared with control and SSRI-treated women. Taken together, these results show that the NGF signaling and downstream pathways in the placenta are affected by SSRI treatment and/or antenatal depression. This might lead to an altered placental function, although the clinical relevance of our findings still needs to be investigated.     

Respiration rate, heart rate, and body temperature values in cynomolgus monkeys (Macaca fascicularis) during barbiturate anesthesia

Respiration rate, heart rate, and body temperature values were obtained from 14 cynomolgus monkeys (Macaca fascicularis) during neurosurgery under barbiturate anesthesia. Vital sign values markedly declined below baseline during the early stages of surgery, steadily increased as surgery progressed and neared completion, and finally returned to baseline by the end of the postsurgical recovery period. There was considerable variability among the 14 monkeys, but the ranking of each monkey relative to the others remained constant across the period of observation. The findings suggested that the cynomolgus monkey may be more sensitive to barbiturates than the rhesus monkey, and cynomolgus monkeys may exhibit considerable individual differences in their sensitivity to barbiturates.     

Behavioral and adrenocortical responses of male cynomolgus and lion-tailed macaques to social stimulation and group formation

Several recent studies indicate that primate species may differ in behavioral, and in some instances physiological, responses to social manipulations. These differences in response dispositions have been interpreted as being based on temperamental differences among species. This report extends previous comparative studies of macaques by describing behavioral contrasts observed between males of two macaque species, lion-tailed and cynomolgus macaques, in response to social manipulations. Males were exposed to a mirror, then visually exposed to conspecific neighbors in all pairwise combinations, and then formed into conspecific social groups. Urine samples were collected in the pairing and group formation conditions for cortisol assay. The cynomolgus demonstrated more affiliative behavior than the lion-tails in all conditions, while the lion-tails tended to exhibit more aggressive behavior. Following group formation cortisol values showed a decreasing trend in the cynomolgus, but not in the lion-tails. The cynomolgus rapidly adapted to group living and relations between them were primarily affiliative. In contrast, no affiliative behavior was ever observed in the lion-tail group, which appeared to be highly stressed by group living and was eventually disbanded.     

Comparison of methods to stimulate ovarian follicular growth in cynomolgus and African green monkeys for collection of mature oocytes

The objective was to compare various gonadotropin-based methods to stimulate ovarian follicular growth in female cynomolgus (n=16) and African green monkeys (n=8) for collection of mature oocytes. On the 1st day of menstruation, the monkeys were treated with 3.75 mg leuprorelin acetate (a GnRH agonist). Starting 2-3 weeks later, ovarian follicular growth was stimulated as follows: (a) 25 IU/kg of human FSH (hFSH) in a glycerol solution given once daily for 9 d; (b) 200 IU of eCG given six times during a 9-d interval; (c) 75 IU/kg hFSH in a glycerol solution given three times (72 h intervals) during a 6-d interval. In addition, the monkeys were given 1200 or 4000 IU of hCG 36 h (Methods A and B) or 60 h (Method C) after the last gonadotropin treatment, and oocyte collection was attempted 36-38 h after hCG. Although there were no significant differences among methods in the number of oocytes collected, in cynomolgus monkeys, hFSH (Methods A and C) was better than eCG (Method B; 12 and 10 versus 7 mature oocytes, respectively), whereas in African green monkeys, eCG (Method B) was more effective than hFSH (Method A; 12 versus 7 mature oocytes). Furthermore, in cynomolgus monkeys, Method C was nearly as effective as Method A; using a glycerol solution as a solvent decreased the frequency of hFSH administration from nine to three times. In conclusion, in cynomolgus and African green monkeys, ovarian response depended on the species and on the individual, and in cynomolgus monkeys, hFSH in a glycerol solvent was effective.     

Peripheral aromatization: studies on controlling factors

Using constant infusions of 3H-labeled androgens and 14C-labeled estrogens with measurements of radiolabeled estrogens in blood and/or urine we have carried out studies on the peripheral aromatization of androgens in humans, nonhuman primates, sheep, and rabbits. In the human, aromatization is increased in women as they become postmenopausal, although the mechanism remains uncertain. In humans and cynomolgus monkeys the administration of ACTH and/or glucocorticoids does not increase peripheral aromatization, but results in a slight decrease in the aromatization of androstenedione. The administration of l-thyroxine to cynomolgus monkeys increases peripheral aromatization of androstenedione from basal, 1.16 +/- 0.15%, to 1.71 +/- 0.14% probably due to increased tissue blood flow. The aromatization of testosterone is not affected, probably due to an increase in sex hormone-binding globulin. Peripheral aromatization occurs to a similar degree in humans, rhesus and cynomolgus monkeys, and baboons, but is much lower in sheep and rabbits. The compound 10-(2-propynyl)-estr-4-ene-3,17-dione is an effective inhibitor of the peripheral aromatization of both androstenedione and testosterone.     

Gender-Specific Effects of Depression and Suicidal Ideation in Prosocial Behaviors

Background

Prosocial behaviors are essential to the ability to relate to others. Women typically display greater prosocial behavior than men. The impact of depression on prosocial behaviors and how gender interacts with those effects are not fully understood. We explored the role of gender in the potential effects of depression on prosocial behavior.

Methods

We examined prosocial behaviors using a modified version of the Trust Game in a clinical population and community controls. Study participants were characterized on the severity of depression and anxiety, presence of suicidal ideation, history of childhood trauma, recent stressful life events, and impulsivity. We correlated behavioral outcomes with gender and clinical variables using analysis of variance and multiple regression analysis.

Results

The 89 participants comprised four study groups: depressed women, depressed men, healthy women and healthy men (n = 16–36). Depressed men exhibited reciprocity more frequently than healthy men. Depression induced an inversion of the gender-specific pattern of self-centered behavior. Suicidal ideation was associated with increased reciprocity behavior in both genders, and enhancement of the effect of depression on gender-specific self-centered behavior.

Conclusions

Depression, particularly suicidal ideation, is associated with reversal of gender-specific patterns of prosocial behavior, suggesting abnormalities in sexual hormones regulation. This explanation is supported by known abnormalities in the hypothalamus-pituitary-adrenal and hypothalamus-pituitary-gonadal axes found in depression.     

Sensitivity to stress-induced reproductive dysfunction is associated with a selective but not a generalized increase in activity of the adrenal axis

Stress-induced reproductive dysfunction is a relatively common cause of infertility in women. In response to everyday life stress, some individuals readily develop reproductive dysfunction (i.e., they are stress sensitive), whereas others are more stress resilient. Female cynomolgus monkeys, when exposed to mild combined psychosocial and metabolic stress (change in social environment + 20% reduced calorie diet), can be categorized as stress sensitive (SS; they rapidly become anovulatory in response to stress), medium stress resilient (MSR; they slowly become anovulatory in response to prolonged stress), or highly stress resilient (HSR; they maintain normal menstrual cycles in response to stress). In this study, we examined whether increased sensitivity to stress-induced reproductive dysfunction is associated with elevated adrenal axis activity by measuring 1) the diurnal release of ACTH and cortisol, 2) ACTH and cortisol in response to an acute psychological stress, 3) the percent suppression of cortisol in response to dexamethasone negative feedback, 4) the diurnal release of ACTH and cortisol following exposure to mild psychosocial and metabolic stress, 5) the concentration of cortisol in hair, and 6) adrenal weight. SS monkeys (n = 5) did not differ from MSR (n = 5) or HSR (n = 7) monkeys in any measurement of baseline HPA axis activity or the integrated measurements of chronic HPA axis activity. However, MSR + SS monkeys (n = 10) did secrete more cortisol than HSR monkeys during the daytime hours (1000-1800) following exposure to a novel social environment and reduced diet. We conclude that increased activity of the HPA axis is unlikely to be the primary mechanism causing increased sensitivity to stress-induced reproductive dysfunction.     

Relationship between body weight and hematological and serum biochemical parameters in female cynomolgus monkeys (Macaca fascicularis).

Obesity is a risk factor triggering a variety of metabolic diseases. Cynomolgus monkeys (Macaca fascicularis) exhibit spontaneous onset of obesity in adulthood, similar to such onset exhibited by humans. To clarify the characteristics accompanying obesity in female cynomolgus monkeys, we used simple and multiple regression analyses to determine the relationship between body weight and hematological and serum biochemical parameters as well as obesity-related hormones, namely, leptin and insulin. Simple regression analysis showed that body weight was significantly (P < 0.05) correlated with leptin level, insulin level, hemoglobin concentration, hematocrit values, mean corpuscular volume, glucose concentration, and triglyceride concentration. In addition, a multiple regression model containing leptin level, insulin level, mean corpuscular volume, and red blood cell count explained 66.9% of the variance in body weight. Therefore, female cynomolgus monkeys show similar obesity characteristics to humans, i.e., obesity is associated with enhanced synthesis and excretion of leptin in adipocytes, high risk of diabetes mellitus, and high levels of hematocytes. Our results indicate that female cynomolgus monkeys are good models for studying obesity in humans.     

Behavioral discrimination between circumgenital odor from peri-ovulatory dominant and anovulatory female common marmosets (Callithrix jacchus)

Social peer groups of callitrichid monkeys [marmosets and tamarins] exhibit intrasexual dominance hierarchies in captivity. This laboratory study employed two-choice behavioral discrimination bioassys to test the hypothesis that scent from female common marmosets contains chemical cues that permit discrimination between dominant females in the peri-ovulatory versus luteal phase of the ovarian cycle and females holding dominant versus subordinate status. When scent from only dominant females was presented, marmosets directed significantly greater amounts of investigatory behavior toward peri-ovulatory scent versus scent collected during the luteal phase of the ovarian cycle. Animals of both sexes demonstrated significant discriminatory behavior between scent deposited by dominant versus subordinate females, but only when the dominant female was in the peri-ovulatory phase of the ovarian cycle. Test animals directed equal amounts of investigative behavior toward scent from luteal-phase dominant females and subordinate females. Female test subjects deposited significantly more scent marks over presented scents than did male subjects, particularly when the scent had been donated by a peri-ovulatory female. Chemical odors specific to the peri-ovulatory and luteal phases of the ovarian cycle may play a role in mediating behavioral interactions among marmosets. Am. J. Primatol. 46:265–284, 1998. © 1998 Wiley-Liss, Inc.     

Sex differences in social interaction behavior following social defeat stress in the monogamous California mouse (Peromyscus californicus)

Stressful life experiences are known to be a precipitating factor for many mental disorders. The social defeat model induces behavioral responses in rodents (e.g. reduced social interaction) that are similar to behavioral patterns associated with mood disorders. The model has contributed to the discovery of novel mechanisms regulating behavioral responses to stress, but its utility has been largely limited to males. This is disadvantageous because most mood disorders have a higher incidence in women versus men. Male and female California mice (Peromyscus californicus) aggressively defend territories, which allowed us to observe the effects of social defeat in both sexes. In two experiments, mice were exposed to three social defeat or control episodes. Mice were then behaviorally phenotyped, and indirect markers of brain activity and corticosterone responses to a novel social stimulus were assessed. Sex differences in behavioral responses to social stress were long lasting (4 wks). Social defeat reduced social interaction responses in females but not males. In females, social defeat induced an increase in the number of phosphorylated CREB positive cells in the nucleus accumbens shell after exposure to a novel social stimulus. This effect of defeat was not observed in males. The effects of defeat in females were limited to social contexts, as there were no differences in exploratory behavior in the open field or light-dark box test. These data suggest that California mice could be a useful model for studying sex differences in behavioral responses to stress, particularly in neurobiological mechanisms that are involved with the regulation of social behavior.     

Do old female monkeys have a specific social role?

The role of the aged in human society has received much attention from gerontologists, and the notion of a social role for aged monkeys is common in primatology. Four hundred and fifty hours of focal animal data were collected on a sample of 40 adult female Japanese monkeys. The animals are semi-free ranging and of known age. These data were analyzed in an attempt to determine whether old females constitute a behaviorally distinct subgroup. Very little behavioral variation based on age could be documented. Where age related variation occurs, it is better explained as a function of youth, rather than as a function of old age. The expectation that old monkeys will occupy a distinct social role because of their advanced age is discussed in terms of biological versus social aging, human versus non human aging, the evolution of behavioral change in old age, and the application of the social role concept to old female monkeys. It is concluded that there is little evidence that the behavior of the aged females differs significantly from that of the other adult females, and it does not appear that the fact of biological aging creates any radically different social situation which would cue the onset of specific role behavior for aged animals.     

Effects of aging on bone mineral content and bone biomarkers in female cynomolgus monkeys.

Age-related changes in bone mineral content and bone biomarkers were assessed over the complete lifespan of female cynomolgus monkeys. The bone mass of the lumbar spine increased linearly from birth to about 2.5 years of age, and this increase gradually slowed thereafter until a peak bone mass was achieved at 9 years of age. The bone mass stabilized after 9 years of age, showing no sign of further reduction with age. In contrast with the significant increase in bone mass before 2.5 years of age, significant decreases occurred in the serum concentrations of the following bone formation markers: intact osteocalcin, bone-specific alkaline phosphatase and amino-terminal propeptide of type I procollagen, but the serum concentration of carboxy-terminal propeptide of type I procollagen did not change significantly throughout the entire lifespan. Concerning the bone resorption markers, the levels of tartrate-resistant acid phosphatase fluctuated throughout the entire lifespan. The skeleton of an aging female monkey undergoes changes similar to those observed in senescent humans, but did not undergo the menopausal changes seen in women. The use of female cynomolgus monkeys to model human skeletal interventions should therefore be undertaken with consideration of the similarities and differences between cynomolgus monkeys and humans.