Aging research using the common marmoset: Focus on aging interventions

Traditional animal models have been used to make seminal discoveries in biomedical research including a better understanding of the biology of the aging process. However, translation of these findings from laboratory to clinical populations has likely been hindered due to fundamental biological and physiological differences between common laboratory animals and humans. Non-human primates (NHP) may serve as an effective bridge towards translation, and short-lived NHP like the common marmoset offer many advantages as models for aging research. Here, we address these advantages and discuss what is currently understood about the changes in physiology and pathology that occur with age in the marmoset. In addition, we discuss how aging research might best utilize this model resource, and outline an ongoing study to address whether pharmaceutical intervention can slow aging in the marmoset. With this manuscript, we clarify how common marmosets might assist researchers in geroscience as a potential model for pre-clinical translation

Aging Phenotypes of Common Marmosets ( Callithrix jacchus

Characterizing the phenotypic changes associated with aging in a short-lived primate is necessary in order to develop better translational models for human health, aging, and disease research. A population of conventionally housed marmoset monkeys was assessed to determine if phenotypes of body composition, hematology, and morphometrical measures were associated with age or risk of death. We found that the cause of mortality in older marmosets was more likely to be due to cardiac and chronic kidney disease than in younger marmosets. Older marmosets have decreased fat mass, morphometric measures, and serum albumin. Older marmosets are more likely to show a modified posture while at rest and this modified posture was significantly associated with an increased risk of imminent death. These assessments provide an initial definition of aged health in marmosets and a base for future translational aging research with this species

Aging Phenotypes of Common Marmosets (Callithrix Jacchus)

Characterizing the phenotypic changes associated with aging in a short-lived primate is necessary in order to develop better translational models for human health, aging, and disease research. A population of conventionally housed marmoset monkeys was assessed to determine if phenotypes of body composition, hematology, and morphometrical measures were associated with age or risk of death. We found that the cause of mortality in older marmosets was more likely to be due to cardiac and chronic kidney disease than in younger marmosets. Older marmosets have decreased fat mass, morphometric measures, and serum albumin. Older marmosets are more likely to show a modified posture while at rest and this modified posture was significantly associated with an increased risk of imminent death. These assessments provide an initial definition of aged health in marmosets and a base for future translational aging research with this species

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

S100B is increased in Parkinson’s disease and ablation protects against MPTP-induced toxicity through the RAGE and TNF-α pathway

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Metabolic Consequences of Long-Term Rapamycin Exposure on Common Marmoset Monkeys (Callithrix Jacchus)

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

The Impact of Aging on the Lung Alveolar Environment, Predetermining Susceptibility to Respiratory Infections

Respiratory infections are one of the top causes of death in the elderly population, displaying susceptibility factors with increasing age that are potentially amenable to interventions. We posit that with increasing age there are predictable tissue-specific changes that prevent the immune system from working effectively in the lung. This mini-review highlights recent evidence for altered local tissue environment factors as we age focusing on increased tissue oxidative stress with associated immune cell changes, likely driven by the byproducts of age-associated inflammatory disease. Potential intervention points are presented

Diet, Digestion and Energy Intake in Captive Common Marmosets (Callithrix jacchus): Research and Management Implications

Common marmosets (Callithrix jacchus) are susceptible to intestinal inflammation which leads to chronic diarrhea, weight loss, and vitamin D deficiency. We examined food intake and digestion in three mixed-sex groups of adult marmosets maintained on three commercial base diets. Animals underwent two consecutive 4-day digestion trials. Body mass stayed constant. Feces and diet were assayed for Mn, fat, and gross energy (GE). Apparent digestibility of dry matter (ADDM) was calculated by the total collection method and from dietary and fecal Mn; the methods produced correlated results (r = 0.658, p \u3c 0.001). Apparent digestibility of energy (ADE) was calculated from ADDM and the GE of feces and diet; apparent digestibility of fat (ADfat) was calculated from ADDM and fecal fat. ADDM and ADE varied by diet (p \u3c 0.001). We found poor digesters on all three diets. The concentration of fecal fat was inversely related to ADE (r = −0.729, p \u3c 0.001). High fecal fat (\u3e10%) was associated with ADfat of zero, consistent with lipid malabsorption. Mean digestible energy intake (DEI) was equal to 1.5 the estimated metabolic rate, but varied widely between individuals. The diet with the fewest animals with high fecal fat had the highest mean DEI and most animals above 450 g, suggesting it may be obesogenic

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

Maternal Weight Affects Placental DNA Methylation of Genes Involved in Metabolic Pathways in the Common Marmoset Monkey (Callithrix jacchus)

Accumulating evidence suggests that dysregulation of placental DNA methylation (DNAm) is a mechanism linking maternal weight during pregnancy to metabolic programming outcomes. The common marmoset, Callithrix jaccus, is a platyrrhine primate species that has provided much insight into studies of the primate placenta, maternal condition, and metabolic programming, yet the relationships between maternal weight and placental DNAm are unknown. Here, we report genome-wide DNAm from term marmoset placentas using reduced representation bisulfite sequencing. We identified 74 genes whose DNAm pattern is associated with maternal weight during gestation. These genes are predominantly involved in energy metabolism and homeostasis, including the regulation of glycolytic and lipid metabolic processes pathways