Publications

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.

Metformin has beneficial effects on several age-related diseases (e.g., diabetes, obesity, cancer) and extends lifespan in nematodes and mice. Acarbose, an FDA-approved agent for treating type 2 diabetes, prevents breakdown of complex carbohydrates. Both compounds have been suggested as potential anti-aging interventions and acarbose has been shown to extend mouse longevity by the Intervention Testing Program (ITP). One potential next step is to assess the effect of these interventions on healthspan and lifespan in non-human primates. The common marmoset (Callithrix jacchus) is a small new world monkey with a relatively short life span and small size, both valuable for the translation potential of this nonhuman primate species for the study of aging and chronic disease. However, the dosing and assessment of potential side effects of either metformin or acarbose in this species have yet to be assessed. This study evaluated the pharmacokinetics of two dosage levels each of metformin or acarbose (given separately) in two small groups of young marmosets (n = 5/group) treated for 24 h to define the pharmacokinetics of each drug. The ability to rapidly and reliably dose socially housed marmosets with an oral form of acarbose or metformin that is well tolerated indicates that this species is a reliable model for testing acarbose and metformin in a safe and efficient way in a long-term intervention.

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 < 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 < 0.001). We found poor digesters on all three diets. The concentration of fecal fat was inversely related to ADE (r = -0.729, p < 0.001). High fecal fat (>10%) 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.

Serum cobalamin and folate concentrations can serve as surrogate markers of gastrointestinal disease in dogs and cats, where they can have diagnostic, therapeutic, and prognostic implications. Chronic disease of the gastrointestinal tract, particularly chronic lymphocytic enteritis (CLE), occurs frequently in captive common marmosets. The aims of this study were to validate a commercially available assay for measuring serum cobalamin and folate concentrations in common marmosets, to establish reference intervals for these analytes in healthy marmosets, and to measure serum concentrations in common marmosets with CLE. The commercial assay was linear, accurate, precise, and reproducible for the measurement of serum cobalamin and folate concentrations in common marmosets. In healthy marmosets, the serum cobalamin concentration ranged from 322 to 2642 pg/mL (n = 35) and serum folate concentration from 54.8 to 786.4 ng/mL (n = 37). Low serum folate concentrations were moderately sensitive (greater than 70%) for CLE, and low serum cobalamin concentrations were moderately (greater than 70%) specific for CLE. Both serum cobalamin and folate concentrations were relatively unchanged in marmosets during 120 to 220 d. Serum cobalamin and folate concentrations were stable for approximately 7 y when samples were stored at -80 °C. Additional studies are warranted to further study the clinical implications of low serum cobalamin and folate concentrations in common marmosets.

The gut microbiome is known to play a significant role in human health but its role in aging remains unclear. The objective of this study was to compare the gut microbiome composition between young adult and geriatric non-human primates (marmosets) as a model of human health and disease. Stool samples were collected from geriatric (8+ years) and young adult males (2-5 years). Stool 16S ribosomal RNA V4 sequences were amplified and sequenced on the Illumina MiSeq platform. Sequences were clustered into operational taxonomic units and classified via Mothur's Bayesian classifier referenced against the Greengenes database. A total of 10 young adult and 10 geriatric marmosets were included. Geriatric marmosets had a lower mean Shannon diversity compared with young marmosets (3.15 vs. 3.46; p = 0.0191). Geriatric marmosets had a significantly higher mean abundance of Proteobacteria (0.22 vs. 0.09; p = 0.0233) and lower abundance of Firmicutes (0.15 vs. 0.19; p = 0.0032) compared with young marmosets. Geriatric marmosets had a significantly higher abundance of Succinivibrionaceae (0.16 vs. 0.01; p = 0.0191) and lower abundance of Porphyromonadaceae (0.07 vs. 0.11; p = 0.0494). In summary, geriatric marmosets had significantly altered microbiome diversity and composition compared with young adult marmosets. Further studies are needed to test microbiome-targeted therapies to improve healthspan and lifespan.

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.

The life history of the common marmoset (Callithrix jacchus) points to this species as a premiere nonhuman primate aging model. In order to take advantage of these features, we require an expanded and refined understanding of aging in this species. The papers in this special issue move this field forward substantially by providing exciting new findings about the aging of the common marmoset and the potential this species offers for revealing aging's secrets and improving the lives of aging humans.

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.

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.

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.