Marmoset as a Model to Study Kidney Changes Associated With Aging.

We evaluated whether the marmoset, a nonhuman primate, can serve as a good model to study aging-related changes in the kidney by employing healthy young and aged marmosets of both sexes. Aging was associated with glomerulosclerosis, interstitial fibrosis, and arteriolosclerosis in both sexes; correspondingly, the content of matrix proteins was increased. Functionally, aging resulted in an increase in urinary albumin and protein excretion. There was a robust correlation between markers of fibrosis and functional changes. We explored signaling pathways as potential mechanistic events. Aging in males, but not in females, was associated with reduced renal cortical activity of AMP-activated protein kinase (AMPK) and a trend toward activation of mechanistic target of rapamycin complex 1 (mTORC1); upstream of AMPK and mTORC1, Akt and IGF-1 receptor were activated. In both sexes, aging promoted kidney activation of transforming growth factor ß-1 signaling pathway. While the expression of cystathionine ß-synthase (CBS), an enzyme involved hydrogen sulfide (H2S) synthesis, was reduced in both aged males and females, decreased H2S generation was seen in only males. Our studies show that the marmoset is a valid model to study kidney aging; some of the signaling pathways involved in renal senescence differ between male and female marmosets.

IACUC review of nonhuman primate research.

This article will detail some of the issues that must be considered as institutional animal care and use committees (IACUCs) review the use of nonhuman primates (NHPs) in research. As large, intelligent, social, long-lived, and non-domesticated animals, monkeys are amongst the most challenging species used in biomedical research and the duties of the IACUC in relation to reviewing research use of these species can also be challenging. Issues of specific concern for review of NHP research protocols that are discussed in this article include scientific justification, reuse, social housing requirements, amelioration of distress, surgical procedures, and humane endpoints. Clear institutional policies and procedures as regards NHP in these areas are critical, and the discussion of these issues presented here can serve as a basis for the informed establishment of such policies and procedures.

The marmoset as a model of aging and age-related diseases.

The common marmoset (Callithrix jacchus) is poised to become a standard nonhuman primate aging model. With an average lifespan of 5 to 7 years and a maximum lifespan of 16½ years, marmosets are the shortest-lived anthropoid primates. They display age-related changes in pathologies that mirror those seen in humans, such as cancer, amyloidosis, diabetes, and chronic renal disease. They also display predictable age-related differences in lean mass, calf circumference, circulating albumin, hemoglobin, and hematocrit. Features of spontaneous sensory and neurodegenerative change--for example, reduced neurogenesis, ß-amyloid deposition in the cerebral cortex, loss of calbindin D(28k) binding, and evidence of presbycusis--appear between the ages of 7 and 10 years. Variation among colonies in the age at which neurodegenerative change occurs suggests the interesting possibility that marmosets could be specifically managed to produce earlier versus later occurrence of degenerative conditions associated with differing rates of damage accumulation. In addition to the established value of the marmoset as a model of age-related neurodegenerative change, this primate can serve as a model of the integrated effects of aging and obesity on metabolic dysfunction, as it displays evidence of such dysfunction associated with high body weight as early as 6 to 8 years of age.

Generation of induced pluripotent stem cells from newborn marmoset skin fibroblasts.

Induced pluripotent stem cells (iPSCs) hold great promise for regenerative medicine. For the application of iPSCs to forms of autologous cell therapy, suitable animal models are required. Among species that could potentially be used for this purpose, nonhuman primates are particularly important, and among these the marmoset offers significant advantages. In order to demonstrate the feasibility of the application of iPSC technology to this species, here we derived lines of marmoset iPSCs. Using retroviral transduction with human Oct4, Sox2, Klf4 and c-Myc, we derived clones that fulfil critical criteria for successful reprogramming: they exhibit typical iPSC morphology; they are alkaline phosphatase positive; they express high levels of NANOG, OCT4 and SOX2 mRNAs, while the corresponding vector genes are silenced; they are immunoreactive for Oct4, TRA-1-81 and SSEA-4; and when implanted into immunodeficient mice they produce teratomas that have derivatives of all three germ layers (endoderm, alpha-fetoprotein; ectoderm, betaIII-tubulin; mesoderm, smooth muscle actin). Starting with a population of 4 x 10(5) newborn marmoset skin fibroblasts, we obtained approximately 100 colonies with iPSC-like morphology. Of these, 30 were expanded sufficiently to be cryopreserved, and, of those, 8 were characterized in more detail. These experiments provide proof of principle that iPSC technology can be adapted for use in the marmoset, as a future model of autologous cell therapy.

Reproduction and aging in marmosets and tamarins.

This chapter presents data on the relations between reproduction and aging in both captive and free-ranging marmosets and tamarins. The relationship is examined from two perspectives. First, the relation of age to physiological impairments in reproductive function is explored. Callitrichid females, in common with many other nonhuman primates, begin to display anovulation associated with follicular depletion at a point relatively close to the maximum life span. Unlike Old World primates, however, they continued to display significant steroidogenic activity in the ovary. There are age effects on some reproductive output variables, such as litter size and inter-birth interval, though the effects are often small. Like other mammals, male marmosets display a change in levels of androgens with age, although the magnitude of the decrease is not large and they actually mount an elevated response to GnRH challenge as they age. We also examined whether age affects either the establishment or maintenance of a breeding position, the factors most important in determining lifetime reproductive success. Infant mortality did increase with increasing parturitions, suggesting that there may have been aging or parturition effects on lactation. Generally, marmoset females were well past the age of sexual maturity at the beginning of the tenure and approaching 8-9 years at the end of it. Reproductive decline did not appear to be a gradual process, but a rather abrupt one, often causing the dismantling of the group. There are potentially interesting relations among maternal age, mass and declining reproductive performance, given the known importance of mass as a determinant of reproductive success in female callitrichids.

Pattern of maternal serum corticotropin-releasing hormone concentration during pregnancy in the common marmoset (Callithrix jacchus).

Corticotropin-releasing hormone (CRH), a potent neuropeptide, is produced by the placenta of anthropoid primates. No other mammals, including prosimian primates, are known to produce placental CRH. In humans, placental CRH appears to play an important role in the progression of pregnancy to parturition. Maternal circulating CRH begins to rise early in pregnancy and increases until parturition. Gorillas and chimpanzees share this pattern of increasing maternal CRH during pregnancy with humans. In humans, chimpanzees, and gorillas, maternal CRH and estradiol concentrations are correlated, consistent with the hypothesis that CRH is involved in the biosynthetic pathway for placental estrogen production. In contrast, in baboons, maternal circulating CRH rises precipitously early in pregnancy and then declines, though CRH is detectable until birth. This research was designed to investigate the pattern of maternal circulating CRH in the common marmoset during pregnancy. Blood samples were taken across gestation from nine subjects over 11 pregnancies, and the plasma was assayed for CRH. The pattern of maternal circulating CRH in the common marmoset was similar to that of the baboon, with a rapid rise starting at about 50 days postconception and a peak at approximately 70 days postconception. By 110 days postconception, CRH concentration had plateaued at a significantly lower value. The peak and mean values for CRH were associated with fetal number (e.g., females gestating triplets had higher values than females gestating twins). Urinary estradiol showed no association with plasma CRH concentration. Marmosets appear to differ from the great apes in this regard, and to share a pattern of maternal CRH during pregnancy with the baboon, indicating that the baboon and marmoset pattern may be ancestral. The function of the early rapid rise of CRH in baboons and marmosets, and the significance of this difference between monkeys and apes, are not known.

Endocrine changes in full-term pregnancies and pregnancy loss due to energy restriction in the common marmoset (Callithrix jacchus).

Common marmosets, a New World primate, respond to a modest energy restriction with early termination of the pregnancy. Within female marmosets, comparisons (n = 6) between a normal, term pregnancy and a restriction-induced aborted pregnancy were used to establish cortisol, free estradiol, and chorionic gonadotropin (CG) as urinary markers of placental and fetal function under these two conditions. Abortions occurred 11-47 d after a 25% energy reduction during midpregnancy for all females. Cortisol concentrations were significantly lower in the last 2 wk for the restricted pregnancy than for matched samples in the normal term pregnancy. Both estradiol and estrone were examined in free and conjugated forms. Only free estradiol showed a significant reduction in mean concentrations during midpregnancy for the restricted females compared with their normal, term pregnancies. Mean CG levels from each female served as an independent marker of placental differentiation and function. CG levels were significantly lower during the 2 wk before abortion compared with matched days from a normal, term pregnancy. These data provide evidence that estradiol and cortisol are useful markers of placental and fetal viability in the common marmoset, and their reduced concentration following energy restriction suggests that restriction is not acting as a classical stressor by increasing cortisol and, subsequently, estradiol concentration.