Publications

Recently, the common marmoset has been proposed as a non-human primate model of aging. Their short lifespan coupled with pathologies that are similar to humans make them an ideal model to understand the genetic, metabolic, and environmental factors that influence aging and longevity. However, many of the underlying physiological changes that occur with age in the marmoset are unknown. Here, we attempt to determine if individual metabolites are predictive of future death and to recapitulate past metabolomic results after a change in environment (move across the country) was imposed on a colony of marmosets. We first determined that low levels of tryptophan metabolism metabolites were associated with risk of death in a 2-year follow-up in the animals, suggesting these metabolites may be used as future biomarkers of mortality. We also discovered that betaine metabolism and methionine metabolism are associated with aging regardless of environment for the animals, or of metabolomic assay technique. These two metabolic pathways are therefore of particular interest to examine as future targets for health and lifespan extending interventions. Many of the pathways associated with age in our first study of marmoset metabolomics were not found to have significant age effects in our second study, suggesting more work is needed to understand the reproducibility of large scale metabolomic studies in mammalian models. Overall, we were able to show that while several metabolomics markers show promise in understanding health and lifespan relationships with aging, it is possible that choice of technique for assay and reproducibility in these types of studies are still issues that need to be examined further.

Executive control is a higher-level cognitive function that involves a range of different processes that are involved in the planning, coordination, execution, and inhibition of responses. Many of the processes associated with executive control, such as response inhibition and mental flexibility, decline with age. Degeneration of white matter architecture is considered to be the one of the key factors underlying cognitive decline associated with aging. Here we investigated how white matter changes of the corpus callosum were related to cognitive aging in common marmosets (Callithrix jacchus). We hypothesized that reduction in myelin thickness, myelin density, and myelin fraction of axonal fibers in the corpus callosum would be associated with performance on a task of executive function in a small sample of geriatric marmosets (n = 4) and young adult marmosets (n = 2). Our results indicated declines in myelin thickness, density, and myelin fraction with age. Considerable variability was detected on these characteristics of myelin and cognitive performance assessed via the detoured reach task. Age-related changes in myelin in Region II of the corpus callosum were predictive of cognitive performance on the detoured reach task. Thus the detoured reach task appears to also measure aspects of corticostriatal function in addition to prefrontal cortical function.

The development of the marmoset as a translational model for healthspan and lifespan studies relies on the characterization of health parameters in young and geriatric marmosets. This cross-sectional study examined health phenotypes in marmosets for five domains of interest for human health and aging: mobility, cognition, metabolism, homeostasis, and immune function. Geriatric marmosets were found to have significant executive function impairment when compared to young animals. While geriatric animals did not show gross abnormalities in mobility and measures of locomotion, their types of movement were altered from young animals. Geriatric marmosets had alterations in cardiac function, with significantly increased mean arterial pressures; metabolism, with significantly lower VO2 ; and suppressed immune function. Further, this study sought to characterize and describe histopathology for both young and geriatric healthy marmosets. Overall this study provides a characterization of health parameters for young and geriatric marmosets which will greatly enhance future aging and interventional testing in 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.

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.

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.

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.

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.

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.

Rapamycin has been shown to extend lifespan in rodent models, but the effects on metabolic health and function have been widely debated in both clinical and translational trials. Prior to rapamycin being used as a treatment to extend both lifespan and healthspan in the human population, it is vital to assess the side effects of the treatment on metabolic pathways in animal model systems, including a closely related non-human primate model. In this study, we found that long-term treatment of marmoset monkeys with orally-administered encapsulated rapamycin resulted in no overall effects on body weight and only a small decrease in fat mass over the first few months of treatment. Rapamycin treated subjects showed no overall changes in daily activity counts, blood lipids, or significant changes in glucose metabolism including oral glucose tolerance. Adipose tissue displayed no differences in gene expression of metabolic markers following treatment, while liver tissue exhibited suppressed G6Pase activity with increased PCK and GPI activity. Overall, the marmosets revealed only minor metabolic consequences of chronic treatment with rapamycin and this adds to the growing body of literature that suggests that chronic and/or intermittent rapamycin treatment results in improved health span and metabolic functioning. The marmosets offer an interesting alternative animal model for future intervention testing and translational modeling.