Corinna N. Ross

Metabolic consequences of the early onset of obesity in common marmoset monkeys.

The common marmoset as a model of early obesity was assessed. The hypotheses that juvenile marmosets with excess adipose tissue will display higher fasting glucose, decreased insulin sensitivity, and decreased ability to clear glucose from the blood stream were tested.

Pharmaceutical inhibition of mTOR in the common marmoset: effect of rapamycin on regulators of proteostasis in a non-human primate

Background Inhibition of mechanistic target of rapamycin (mTOR) has emerged as a viable means to lengthen lifespan and healthspan in mice, although it is still unclear whether these benefits will extend to other mammalian species. We previously reported results from a pilot experiment wherein common marmosets (Callithrix jacchus) were treated orally with rapamycin to reduce mTOR signaling in vivo in line with previous reports in mice and humans. Further, long-term treatment did not significantly alter body weight, daily activity, blood lipid concentrations, or glucose metabolism in this cohort. Methods In this study, we report on the molecular consequences of rapamycin treatment in marmosets on mechanisms that regulate protein homeostasis (proteostasis) in vivo. There is growing appreciation for the role of proteostasis in longevity and for the role that mTOR plays in regulating this process. Tissue samples of liver and skeletal muscle from marmosets in our pilot cohort were assessed for expression and activity of components of the ubiquitin-proteasome system, macroautophagy, and protein chaperones. Results Rapamycin treatment was associated with increased expression of PSMB5, a core subunit of the 20S proteasome, but not PSMB8 which is involved in the formation of the immunoproteasome, in the skeletal muscle and liver. Surprisingly, proteasome activity measured in these tissues was not affected by rapamycin. Rapamycin treatment was associated with an increased expression of mitochondria-targeted protein chaperones in skeletal muscle, but not liver. Finally, autophagy was increased in skeletal muscle and adipose, but not liver, from rapamycin-treated marmosets. Conclusions Overall, these data show tissue-specific upregulation of some, but not all, components of the proteostasis network in common marmosets treated with a pharmaceutical inhibitor of mTOR.

Take the monkey and run

BACKGROUND The common marmoset (Callithrix jacchus) is a small, New World primate that is used extensively in biomedical and behavioral research. This short-lived primate, with its small body size, ease of handling, and docile temperament, has emerged as a valuable model for aging and neurodegenerative research. A growing body of research has indicated exercise, aerobic exercise especially, imparts beneficial effects to normal aging. Understanding the mechanisms underlying these positive effects of exercise, and the degree to which exercise has neurotherapeutic effects, is an important research focus. Thus, developing techniques to engage marmosets in aerobic exercise would have great advantages. NEW METHOD Here we describe the marmoset exercise ball (MEB) paradigm: a safe (for both experimenter and subjects), novel and effective means to engage marmosets in aerobic exercise. We trained young adult male marmosets to run on treadmills for 30 min a day, 3 days a week. RESULTS Our training procedures allowed us to engage male marmosets in this aerobic exercise within 4 weeks, and subjects maintained this frequency of exercise for 3 months. COMPARISON WITH EXISTING METHODS To our knowledge, this is the first described method to engage marmosets in aerobic exercise. A major advantage of this exercise paradigm is that while it was technically forced exercise, it did not appear to induce stress in the marmosets. CONCLUSIONS These techniques should be useful to researchers wishing to address physiological responses of exercise in a marmoset model.

Behavioral phenotypes associated with MPTP induction of partial lesions in common marmosets (Callithrix jacchus)

HighlightsBehavioral phenotypes for a partial MPTP model in the marmoset are investigated.We identify non‐motor symptoms including cognitive, olfactory, and social change.Socially housed marmosets present a valid model for evaluation of PD treatments. Abstract Parkinson’s disease is a chronic neurodegenerative disorder with the core motor features of resting tremor, bradykinesia, rigidity, and postural instability. Non‐motor symptoms also occur, and include cognitive dysfunction, mood disorders, anosmia (loss of smell), and REM sleep disturbances. As the development of medications and other therapies for treatment of non‐motor symptoms is ongoing, it is essential to have animal models that aid in understanding the neural changes underlying non‐motor PD symptoms and serve as a testing ground for potential therapeutics. We investigated several non‐motor symptoms in 10 adult male marmosets using the MPTP model, with both the full (n = 5) and partial (n = 5) MPTP dosing regimens. Baseline data in numerous domains were collected prior to dosing; assessments in these same domains occurred post‐dosing for 12 weeks. Marmosets given the partial MPTP dose (designed to mimic the early stages of the disease) differed significantly from marmosets given the full MPTP dose in several ways, including behavior, olfactory discrimination, cognitive performance, and social responses. Importantly, while spontaneous recovery of PD motor symptoms has been previously reported in studies of MPTP monkeys and cats, we did not observe recovery of any non‐motor symptoms. This suggests that the neurochemical mechanisms behind the non‐motor symptoms of PD, which appear years before the onset of symptoms, are independent of the striatal dopaminergic transmission. We demonstrate the value of assessing a broad range of behavioral change to detect non‐motor impairment, anosmia, and differences in socially appropriate responses, in the marmoset MPTP model of early PD.

Obesity, Metabolism, and Aging: A Multiscalar Approach

Obesity contributes to the aging process through the alteration of metabolic pathways evidenced biochemically in the relationship between caloric restriction and longevity. Humans have entered into an era of metabolism and aging entirely unprecedented in their evolution, with a diet that, for many, contains a majority of calories as sugar and yields an expected lifespan of over 80years in industrialized nations. Deeply embedded in the complex issue of obesity are questions of behavior, causality versus correlation, and appropriate models. For example, are primates a better reference than mice for studying metabolic connections between obesity and aging? We consider those issues from the standpoint of life-history theory, especially implications of the interplay of refined sugar and socioeconomic disparities for the future of human health.

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 β-1 signaling pathway. While the expression of cystathionine β-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.

Long-term treatment with the mTOR inhibitor rapamycin has minor effect on clinical laboratory markers in middle-aged marmosets

Interventions to extend lifespan and improve health with increasing age would have significant impact on a growing aged population. There are now several pharmaceutical interventions that extend lifespan in laboratory rodent models with rapamycin, an inhibitor of mechanistic target of rapamycin (mTOR) being the most well studied. In this study, we report on the hematological effects in a cohort of middle‐aged common marmosets (Callithrix jacchus) that were enrolled in a study to test the effects of daily rapamycin treatment on aging in this species. In addition, we assessed whether sex was a significant factor in either baseline assessment or as an interaction with rapamycin treatment. Among our cohort at baseline, we found few differences in either basic morphology or hematological markers of blood cell counts, metabolism or inflammation between male and female marmosets. After dosing with rapamycin, surprisingly we found trough blood concentrations of rapamycin were significantly lower in female compared to male marmosets. Despite this pharmacological difference, both sexes had only minor changes in cellular blood counts after 9 months of rapamycin. These data then suggest that the potential clinical hematological side effects of rapamycin are not likely outcomes of long‐term rapamycin in relatively healthy, middle‐aged marmosets.

The Common Marmoset Monkey: Avenues for Exploring the Prenatal, Placental and Postnatal Mechanisms in Developmental Programming of Pediatric Obesity

Animal models have been critical in building evidence that the prenatal experience and intrauterine environment are capable of exerting profound and permanent effects on metabolic health through developmental programming of obesity. However, despite physiological and evolutionary similarities, nonhuman primate models are relatively rare. The common marmoset monkey ( Callithrix jacchus) is a New World monkey that has been used as a biomedical model for well more than 50 years and has recently been framed as an appropriate model for exploring early-life impacts on later health and disease. The spontaneous, multifactorial, and early-life development of obesity in the common marmoset make it a valuable research model for advancing our knowledge about the role of the prenatal and placental mechanisms involved in developmental programming of obesity. This paper provides a brief overview of obesity in the common marmoset, followed by a discussion of marmoset reproduction and placental characteristics. We then discuss the occurrence and utility of variable intrauterine environments in developmental programming in marmosets. Evidence of developmental programming of obesity will be given, and finally, we put forward future directions and innovations for including the placenta in developmental programming of obesity in the common marmoset.

The development of a specific pathogen free (SPF) barrier colony of marmosets (Callithrix jacchus) for aging research

A specific pathogen free (SPF) barrier colony of breeding marmosets (Callithrix jacchus) was established at the Barshop Institute for Longevity and Aging Studies. Rodent and other animal models maintained as SPF barrier colonies have demonstrated improved health and lengthened lifespans enhancing the quality and repeatability of aging research. The marmosets were screened for two viruses and several bacterial pathogens prior to establishing the new SPF colony. Twelve founding animals successfully established a breeding colony with increased reproductive success, improved health parameters, and increased median lifespan when compared to a conventionally housed, open colony. The improved health and longevity of marmosets from the SPF barrier colony suggests that such management can be used to produce a unique resource for future studies of aging processes in a nonhuman primate model.