In humans, age-related accumulations of physical deficits are often characterized by frailty indices, which predict increased risk for neurodegeneration characteristic of Alzheimer's disease (AD). However, social capabilities also may diminish, with considerable variation in inter-individual trajectories of decline and AD risk. Social frailty has recently been proposed in humans and mice to characterize the severity of social impairments with age; however, no index of social frailty exists for nonhuman primates (NHPs). This represents a significant gap in the literature, as NHPs provide important translational opportunities to study brain-body relationships that promote healthy versus pathological aging. Here, we developed a novel index of social frailty in female vervet monkeys ( Chlorocebus aethiops sabaeus ) using six components of social behavior measuring positive interactions, agonistic interactions and social isolation. Members of this study comprise the Wake Forest Aging Vervet Cohort, which includes 30+ captive females ranging from middle- to very old age (8-29 years). Subjects live with their families in large, multi-matrilineal social groups. We first tested whether social frailty in vervets recapitulated age-related changes observed in humans. Next, we determined the cross-sectional relationships between social frailty and neuroanatomy derived from structural MRI. Finally, we tested whether social frailty predicted biomarkers associated with AD (MesoScale Discovery Platform: Ab40, Ab42, Ab42:40, ptau181, NfL, and GFAP) in CSF at approximately one year follow-up. The social frailty index increased with age (t= 3.695, p  <0.001). Social frailty was positively associated with CSF volumes (t= 2.163 p  = 0.035) and negatively associated with cortical gray matter (t=-4.261, p  <0.001), white matter (t=-2.591, p  = 0.013), and cerebellar (t=-3.716, p  <0.001) volumes. Social frailty also predicted several CSF biomarkers associated with AD. Higer social frailty predicted higher levels of phosphorylated tau (t=2.304, p  = 0.024) but lower Ab42 (t=-2.345 p  = 0.022) and Ab40 (t=-2.138, p  = 0.036). Social frailty was also associated with elevated NfL and GFAP in CSF; however, the associations did not reach statistical significance ( p 's <0.10). Like humans, some vervets may exhibit increasing socially frailty with age. These unhealthy aging trajectories - characterized by fewer positive interactions, social isolation, and agonistic interactions - are associated with AD neuroimaging and biofluid biomarkers.

Alzheimer’s disease is characterized by the deposition of amyloid-beta (Aβ) plaques, necessitating early detection and reliable biomarkers for effective intervention. Non-human primates, particularly aged vervet monkeys, offer valuable models for studying age-related Aβ pathology due to their close phylogenetic relationship to humans and similar neuropathological features. This study assessed the utility of [18F]FC119S, a novel Aβ-targeting PET radiotracer, in aged vervet monkeys. The radiochemistry of [18F]FC119S was optimized and automated to ensure high radiochemical purity and molar activity. PET/MRI imaging was performed to evaluate tracer uptake, distribution, and washout kinetics. Correlations between [18F]FC119S uptake and cerebrospinal fluid (CSF) and plasma biomarkers—including Aβ42/40 ratio, pTau181, neurofilament light chain (NfL), and pTau181/Aβ42 ratio—were analyzed. Autoradiography was conducted to validate regional tracer binding in brain tissues. [18F]FC119S demonstrated high brain uptake, rapid washout, and widespread cortical distribution in vervet monkeys, mirroring patterns observed in human studies. Tracer uptake showed negative associations with CSF Aβ42/40 ratio in Aβ-affected regions, and significant positive correlations with CSF pTau181 and CSF pTau181/Aβ42 ratio in the temporal lobe. Additionally, significant positive correlations were observed between [18F]FC119S uptake and CSF NfL in the anterior cingulate gyrus, parietal, and occipital lobes. Autoradiography confirmed elevated tracer binding in specific brain regions of older vervets with low CSF Aβ42 compared to younger counterparts. These findings validate [18F]FC119S as a promising PET radiotracer for tracking Aβ deposition in aged vervet monkeys. Its imaging characteristics and biomarker correlations support its translational potential for Alzheimer’s disease research and early diagnostic applications.

Insulin resistance (IR) is associated with abnormal tau-phosphorylation and IR markers in AD brain co-localize with neurofibrillary tangles. One strategy to overcome brain IR is to increase brain insulin is via intranasal insulin (INI) administration using specialized intranasal devices that deliver insulin to the brain. Our recent INI vs. placebo-controlled double-blinded clinical trial in MCI/AD showed that INI improved CSF biomarkers and slowed symptom progression over the placebo group treated with one type of delivery device (with no benefit with another). While these studies highlight the potential of INI for therapeutic applications, methods are needed to verify the successful INI delivery with specific devices. Here we report our novel [ 68 Ga]-NOTA-insulin-based brain PET imaging and whole-body dosimetry through intranasal route in healthy vervets using the Aptar Cartridge Pump System (CPS) device for the first time. Human-grade insulin was chelated with NOTA and radiolabeled with [ 68 Ga]. 0-90min and 0-3h PET scans were conducted for brain and whole-body dosimetry in healthy vervets (n=4/sex, 9-12 y) after intranasal administration (2 puffs per nostril) of [ 68 Ga]-NOTA-insulin (25-37 MBq) through the Aptar device. Blood glucose, oxygen, heartbeat, and temperature were collected throughout the scan. Standard uptake values (SUVs), time-activity curves (TACs), and standard dosimetry organ doses were calculated. [ 68 Ga]-NOTA-insulin radiochemistry was fully-optimized: shorter reaction times (∼6-7min), lower insulin mass (2-4 units), high radiochemical purity (>99%), and molar activity (108 GBq/µmol). No significant changes were observed in vitals recorded. PET/MRI images showed brain penetration; SUV whole-brain=0.29±0.11, hippocampus=0.18±0.05, cortex=0.21±0.08, choroid plexus=0.38±0.11, and cerebellum=0.09±0.01. TACs showed that radioactivity peaked in brain within 15-20min of radiotracer administration and washed out by 90 min. Dosimetry showed nasal cavity and eyes as critical organs and effective dose=0.11 mSv/MBq. No sex differences were seen in brain uptake or dosimetry parameters. Brain PET and whole-body dosimetry PET scans of [ 68 Ga]-NOTA-insulin in vervets demonstrate brain penetration and favorable distribution of INI respectively. This preliminary data provides critical information for translating [ 68 Ga]-NOTA-insulin PET with intranasal delivery to humans using the Aptar device. This strategy will create a new paradigm for understanding the INI in AD pathogenesis and advance novel therapeutic platforms.

Background African green monkeys (AGMs, also known as vervets, Cholorocebus aethiops sabaeus) have been used in a variety of biomedical research studies. The aim of this study was to generate a reference for normal organ weights and percentage organ weights in AGMs of different age categories and sex. Methods The organ weights were compiled from 479 AGMs (285 females and 194 males) from 2004 to 2021. Age and sex differences of absolute and relative organ weights were analyzed using analysis of variance. Results The findings demonstrate that males had higher body and organ weights than age-matched females, but relative organ weights did not differ between males and females. At maturity, adrenal gland, brain, kidney, liver, thymus, and thyroid gland weights as a percentage of body weight declined, but relative weights of prostate gland, testes, and uterus were higher. Conclusion These data should be beneficial to biomedical researchers and pathologists working with AGMs.

There is a critical need to generate age- and sex-specific survival curves to characterize chronological aging consistently across nonhuman primates (NHP) used in biomedical research. Sex-specific Kaplan-Meier survival curves were computed in 12 translational aging models: baboon, bonnet macaque, chimpanzee, common marmoset, coppery titi monkey, cotton-top tamarin, cynomolgus macaque, Japanese macaque, pigtail macaque, rhesus macaque, squirrel monkey, and vervet/African green. After employing strict inclusion criteria, primary results are based on 12,269 NHPs that survived to adulthood and died of natural/health-related causes. A secondary analysis was completed for 32,616 NHPs that died of any cause. Results show a pattern of reduced male survival among catarrhines (African and Asian primates), especially macaques, but not platyrrhines (Central and South American primates). For many species, median lifespans were lower than previously reported. An important consideration is that these analyses may offer a better reflection of healthspan than lifespan since research NHPs are typically euthanized for humane welfare reasons before their natural end of life. This resource represents the most comprehensive characterization of sex-specific lifespan and age-at-death distributions for 12 biomedically relevant species, to date. These results clarify relationships among NHP ages and provide a valuable resource for the aging research community, improving human-NHP age equivalencies, informing investigators of expected survival rates, providing a metric for comparisons in future studies, and contributing to understanding of factors driving lifespan differences within and among species.

In humans, social integration wanes with age, a pattern hypothesized to stem from cognitive or physical decrements. Social isolation increases dementia risk. Nonhuman primates provide important translational opportunities to study brain-body relationships that may promote healthy or pathological aging. Vervet monkeys ( Chlorocebus sabaeus ), like humans, have complex central nervous systems and naturally experience cognitive, functional, and neuroanatomical changes with age. These changes often recapitulate characteristics of early Alzheimer’s disease (AD), including Aβ accumulation in the brain, reduced CSF Aβ, and greater Aβ plaque burdens accompanied by reduced brain volumes. We studied 25 females, aged 8-29 years (middle to very old-aged), living in long term, stable, social groups. Using a cross-sectional study design, we tested whether cognitive (executive function and working memory) or physical (gait speed) function mediated the effects of age on social behavior. We also used T1-weighted structural MRI to test whether the cortical thickness of an AD-signature region of interest (“meta-ROI”) predicted social participation at one year follow-up. Cognitive (executive function: b = -0.603; p = 0.038; working memory: b = -0.537; p<0.001) and physical (gait speed: (b = -1.005; p = 0.043) function were negatively associated with age. Time spent in affiliative behavior was inversely related to age (b = -0.723; p = 0.009), whereas time spent alone was higher for older-aged monkeys (b = 0.723; p = 0.009). Time spent grooming others decreased with age (b = -0.217; p<0.001), but time receiving grooming did not (b = -0.057; p = 0.333). The number of social partners groomed diminished in aged subjects (b = -0.145; p<0.001). The relationships between age and sociality were mediated, in part, by cognitive function: higher degrees of executive function had a positive mediating effect on time spent in grooming interactions (b = 0.120; p = 0.047). Conversely, social participation was not mediated by physical performance. Finally, thinner cortices in the meta-ROI predicted greater social isolation (t = -2.199; p = 0.038) and fewer numbers of social partners (z = -2.319; p = 0.020) at one year follow-up. These results suggest that: 1) cognitive, physical, and social function of vervets decline with age like humans; 2) aging vervets are not socially excluded but decreasingly engage in social behavior; and 3) cognitive deficits stemming from cortical gray matter deficits may underlie the relationship between aging and social decline.

Nonhuman primates (NHPs) are valuable models for studying healthspan, including frailty development. Frailty metrics in people centers on functional measures, including usual gait speed which can be predictive of all-cause mortality. This concept that physical competencies are able to prognosticate an individual's health trajectory over chronologic aging is well-accepted and has led to refinements in how physical function is evaluated, and include measures of strength and power along with walking speed. NHP studies of aging require evaluation of physical function, which can be difficult in field and research settings. We compared stair climb velocity to usual walking speed in 28 peri-geriatric to geriatric NHPs, as incorporating a climbing obstacle integrates multiple components of physical function: isolated leg and back strength, proprioception, balance, and range of motion. We find that stair climbing speed was reliable between observers, and whether timing was in-person take from video capture. The stair climb rates were 50% more associated with chronological age than walking speed (R = -0.68 vs. -0.45) and only stair climbing speeds were retained as predictive of age when walking speed and bodyweight were included in multivariate models (overall R2  = 0.44; p < 0.0001). When comparing young (10-16 years) versus geriatric (16-29 years) stair climbing speed was significantly different (p < 0.001), while walking speeds only tended to be slower (p = 0.12) suggesting that the additional challenge of a stair climb better unmasks subclinical frailty development that usual walking speed.

In humans, social participation and integration wane with advanced age, a pattern hypothesized to stem from cognitive or physical decrements. Similar age-related decreases in social participation have been observed in several nonhuman primate species. Here, we investigated cross-sectional age-related associations between social interactions, activity patterns, and cognitive function in 25 group-living female vervets (a.k.a. African green monkeys, Chlorocebus sabaeus ) aged 8–29 years. Time spent in affiliative behavior decreased with age, and time spent alone correspondingly increased. Furthermore, time spent grooming others decreased with age, but the amount of grooming received did not. The number of social partners to whom individuals directed grooming also decreased with age. Grooming patterns mirrored physical activity levels, which also decreased with age. The relationship between age and grooming time was mediated, in part, by cognitive performance. Specifically, executive function significantly mediated age’s effect on time spent in grooming interactions. In contrast, we did not find evidence that physical performance mediated age-related variation in social participation. Taken together, our results suggest that aging female vervets were not socially excluded but decreasingly engaged in social behavior, and that cognitive deficits may underlie this relationship.

G-protein-coupled receptor 119 (GPR119) has emerged as a promising target for treating type 2 diabetes mellitus. Activating GPR119 improves glucose homeostasis, while suppressing appetite and weight gain. Measuring GPR119 levels in vivo could significantly advance GPR119-based drug development strategies including target engagement, occupancy, and distribution studies. To date, no positron emission tomography (PET) ligands are available to image GPR119. In this paper, we report the synthesis, radiolabeling, and preliminary biological evaluations of a novel PET radiotracer [18F]KSS3 to image GPR119. PET imaging will provide information on GPR119 changes with diabetic glycemic loads and the efficacy of GPR119 agonists as antidiabetic drugs. Our results demonstrate [18F]KSS3's high radiochemical purity, specific activity, cellular uptake, and in vivo and ex vivo uptake in pancreas, liver, and gut regions, with high GPR119 expression. Cell pretreatment with nonradioactive KSS3, rodent PET imaging, biodistribution, and autoradiography studies showed significant blocking in the pancreas showing [18F]KSS3's high specificity.

Respiratory syncytial virus (RSV) is a leading cause of severe respiratory disease for which no licensed vaccine is available. We have previously shown that a prefusion (preF) conformation-stabilized RSV F protein antigen and an adenoviral vector encoding RSV preF protein (Ad26.RSV.preF) are immunogenic and protective in animals when administered as single components. Here, we evaluated a combination of the 2 components, administered as a single injection. Strong induction of both humoral and cellular responses was shown in RSV-naïve and pre-exposed mice and pre-exposed African green monkeys (AGMs). Both components of the combination vaccine contributed to humoral immune responses, while the Ad26.RSV.preF component was the main contributor to cellular immune responses in both mice and AGMs. Immunization with the combination elicited superior protection against RSV A2 challenge in cotton rats. These results demonstrate the advantage of a combination vaccine and support further clinical development.

OBJECTIVE:Time-restricted feeding (TRF), whereby caloric intake is limited to a <12-hour window, is a potential regimen to ameliorate metabolic syndrome and cardiovascular disease (CVD) risk co-occurring with aging and with obesity. Early TRF (eTRF; early morning feeding followed by overnight fasting) times calorie consumption with hepatic circadian gene expression rhythms. Brief TRF trials demonstrate that high-density lipoprotein (HDL) cholesterol increases similar to diet/exercise interventions, which may impart beneficial CVD effects. Using a nonhuman primate (NHP) model, the efficacy of eTRF to raise HDL and increase plasma cholesterol efflux capacity (CEC) (primarily mediated by cholesterol efflux to HDL particles, a process that is inversely associated with CVD risk) was examined. METHODS:Adult (8-16 years old, n = 25) and geriatric (≥17 years old) NHPs were randomized to ad libitum feeding or eTRF for 12 months, and relevant body composition, glycemic control, and plasma HDL cholesterol levels and CEC were measured. RESULTS:Impaired CEC was found in geriatric NHPs. eTRF induced larger-sized HDL particles, increased HDL apolipoprotein A-1 content, lowered triglyceride concentrations, and increased plasma CEC (primarily to HDL particles) in both adult and geriatric NHPs without changes in glycemic control or body composition. CONCLUSIONS:A beneficial effect of eTRF on increasing HDL CEC in NHPs was demonstrated.

Yersinia enterocolitica is a Gram-negative bacterium that typical results in enterocolitis in humans and poses significant worldwide risks to public health. An outbreak of yersiniosis in the Vervet/African green monkey colony at the WFSM during the winter of 2015–2016 accounted for widespread systemic infection with high morbidity and mortality. Most of the cases had extensive necrosis with suppuration and large colonies of bacilli in the large bowel and associated lymph nodes; however, the small intestine, stomach, and other organs were also regularly affected. Positive cultures of Yersinia enterocolitica were recovered from affected tissues in 20 of the 23 cases. Carrier animals in the colony were suspected as the source of the infection because many clinically normal animals were culture-positive during and after the outbreak. In this study, we describe the gross and histology findings and immune cell profiles in different organs of affected animals. We found increased numbers of myeloid-derived phagocytes and CD11C-positive antigen-presenting cells and fewer adaptive T and B lymphocytes, suggesting an immunocompromised state in these animals. The pathogen-mediated microenvironment may have contributed to the immunosuppression and rapid spread of the infection in the vervets. Further studies in vervets could provide a better understanding of Yersinia-mediated pathogenesis and immunosuppression, which could be fundamental to understanding chronic and systemic inflammatory diseases in humans.

Maternal parity can impact offspring growth, but the mechanisms driving this effect are unclear. Here, we test the hypothesis that vertically transmitted microbiota may be one potential mechanism. We analyzed 118 fecal and milk samples from mother-offspring vervet monkey dyads across the first 6 months of life. Despite poorer milk production, off spring born to low parity females grew larger than their counterparts. These offspring exhibited reduced alpha diversity in the first days of life, stronger seeding of maternal milk microbiota, Bacteroides fragilis dominance, and a greater abundance of glycan utilization pathways. Moreover, the attainment of greater body mass by 6 months of age was mediated by reduced early life alpha diversity and B. fragilis dominance. This work demonstrates that the establishment of a specialized, milk-oriented gut microbiota promotes infant growth and suggests an evolutionarily conserved developmental role of B. fragilis in primates.

G-protein-coupled receptors (GPCRs) plays a key role in regulating glucose metabolism. While GPR119 (an important GPCR) agonists have shown potential for improving neurologic and cognitive function in patients with AD and type2 diabetes mellitus (T2DM), clinical interventions targeting GPR119 will require accurate in vivo measures such as PET imaging. We recently synthesized a series of novel piperdine analogs, identifying two analogs (T1 and T2) with high GPR119 binding potency (2-5 nM) for PET radiochemistry. Here we report their radiochemistry and initial biological evaluations in neuronal cells, normal rodents, and monkeys (vervets). [ 18 F]T1/T2 radiochemistry was performed in TRASIS-AIO automated module following [ 18 F]¯-based nucleophilic substitution of corresponding precursors. [ 18 F]T1 and T2 in vitro assays were performed in three patient-derived cell lines with different GPR119 expression (MDM-MD-23198%) and specific activities (∼3800-4500 mCi/µmol), decay corrected to end of synthesis. Radioactive cell uptake was lower in MDM-MD-231 cells (lowest GPR119 expression) and higher in HepG2 cells (higher GPR119 expression); uptake also significantly increased with GPR119 agonists and T1/T2 treatments compared to baseline. [ 18 F]T2 showed slightly better brain uptake in mice compared to [ 18 F]T1 (SUV max = 0.35±0.07 Vs. 0.55±0.09 g/mL). Biodistribution of [ 18 F]T2 (%ID/mg = 1.01±0.09) also showed high brain uptake. SUV max (avg=2.6±0.1 g/mL) and TACs of both [ 18 F]T1 and [ 18 F]T2 in monkey brains demonstrated rapid distribution across BBB within 10 min and favorable clearance within 90 min of tracer injection ( Fig 1 ). Radiochemistry was successfully automated and optimized. Cell uptake showed direct relationships between radiotracer uptake and GPR119 expression. MicroPET imaging, biodistribution in rodents and monkey PET imaging demonstrated excellent brain uptake and favorable pharmacokinetics, indicating BBB penetration. These data suggest for the first time that [ 18 F]T1 and T2 have potential for imaging GPR119 in brains of humans with AD or T2DM.

Dual declines in gait speed and cognitive performance are associated with increased risk of developing dementia. Characterizing the patterns of such impairments therefore is paramount to distinguishing healthy from pathological aging. Nonhuman primates such as vervet/African green monkeys ( Chlorocebus aethiops sabaeus ) are important models of human neurocognitive aging, yet the trajectory of dual decline has not been characterized. We therefore (1) assessed whether cognitive and physical performance (i.e., gait speed) are lower in older aged animals; (2) explored the relationship between performance in a novel task of executive function (Wake Forest Maze Task—WFMT) and a well-established assessment of working memory (delayed response task—DR task); and (3) examined the association between baseline gait speed with executive function and working memory at 1-year follow-up. We found (1) physical and cognitive declines with age; (2) strong agreement between performance in the novel WFMT and DR task; and (3) that slow gait is associated with poor cognitive performance in both domains. Our results suggest that older aged vervets exhibit a coordinated suite of traits consistent with human aging and that slow gait may be a biomarker of cognitive decline. This integrative approach provides evidence that gait speed and cognitive function differ across the lifespan in female vervet monkeys, which advances them as a model that could be used to dissect relationships between trajectories of dual decline over time.

Vervets (Chlorocebus spp.), also known as African green monkeys or savanna monkeys, are Old World monkeys that are frequently studied in biomedical research. Research areas have included immunology and vaccine development, neuroscience and Alzheimer’s disease, obesity and metabolism, and genetics, among others. There are multiple species/subspecies of vervets, and their taxonomy and common name usage are still actively debated. Vervets are one of the most widespread of the African monkeys, found across many regions of sub-Saharan Africa, with feral subpopulations located within the Caribbean. They live in multimale, multifemale social groups. Females are philopatric, with groups consisting of matrilines of closely related females, while males disperse at adolescence. Vervets are highly adaptable and are able to utilize a wide range of diets and habitats. While similar to macaques and baboons in many ways, there are a few key differences: vervets are territorial, semi-arboreal, and have less rigid dominance hierarchies; female vervets have relatively long canines and have no overt signs of menstruation or ovulation; and vervets have some unique patterns of behavior and vocalization not seen in other Old World monkeys. Understanding the natural history and unique characteristics of vervets should help enhance the well-being of these species in captivity.