During the past century, the average lifespan of people living in industrialized countries has increased substantially.  These gains have been achieved by improvements in public health, suppression of infectious disease and increased food/water security.  These advances have led to the elderly becoming one of the fastest-growing segments of society.  However, significant challenges remain, as evidenced by the continual emergence of novel pathogens and moreover, finding the means of extending the “healthspan” of retirees.  The latter includes amelioration of fragility and chronic, progressive illnesses so that functionality extends well into retirement.  This situation has a significant social-economic impact, with federal spending on elderly health care continuing to rise. 

Historically, the long-term forecast of the increase in the aged population helped lead to the creation of the National Institute on Aging (NIA) in 1974.  While the NIA supports clinically based research on the biology of aging and its associated diseases, basic research on aging is also critical.  For example, clinically based studies are difficult to control, with heterogeneity in genetics, life histories, and exposure to different environments.  Model systems address some of these issues and help explore fundamental mechanisms.  Moreover, to assist with this process, the NIA makes available any number of resources, including genetically defined rodent strains and higher vertebrate species like the nonhuman primate (NHP) are also included, due to their phylogenetic relationship to humans.  

The NHP model is highly translational to the clinic, sharing similar genetics, anatomy, physiology, and a long lifespan compared to rodents.  Recently, the NIA has added support for the marmoset model, as a shorter-lived alternative to longer-lived old-world monkeys in the quest for faster results.  NIA support for aged primates leverages the resources, expertise, and infrastructure at several National Primate Research Centers, including ONPRC.   With the concurrent support of ONPRC, the Aging Primate Resource (APR), created in 1999, enhances NHP aging research, with the following goals: 

• Manage the enrollment and maintenance of animals into the aging program. 
• Provide technical and veterinary consultation for research projects on aging. 
• Support project development and coordinate animal assignments.  
• Provide support on aging research at ONPRC and for external NIA grantees. 
• Promote collaborative efforts in basic and clinical science. 
• Non-invasively collect biomarker information. 
• Maintain an aged nonhuman primate tissue archive for scientific discovery. 
• Explore the ONPRC database for describing aging in the primate model. 
• Design and maintain a portion of the aging colony for the establishment of longitudinal biomarkers of aging. 

Recent studies using the APR have examined age effects on functional-anatomical changes, including the interaction of diet, reproductive senescence, and hormone treatment on the brain, immunity, circadian rhythms, sleep disruption, stroke, cancer, cardiovascular disease, macular degeneration, genomics, as well as establishing the parameters of normative aging both locally and with affiliate researchers. 

For tissue requests, and/or questions on animal availability or collaborative projects contact Steven Kohama, Ph.D. at kohamas@ohsu.edu.

Obesity is a complex, multifactorial disease that is defined by excessive adiposity. Increased BMI is linked to an increased risk for co-morbidities like type 2 diabetes mellitus, cardiovascular disease, stroke and others, referred to as metabolic disease. The macaque is a unique model for clinically translational research in the field of obesity based on metabolic similarities between macaques and humans that are not always shared in rodent models. The Obese Resource generates and provides access to diet-induced obese (DIO) nonhuman primates (NHP) to support research involving metabolism for diverse projects across many different fields. 

Obese macaques are produced by providing a palatable diet that is higher in saturated fatty acids, referred to as Western style diet (WSD) or high fat diet (HFD). Baseline and routine longitudinal assessments of metabolism are performed to phenotypically characterize each animal. Procedures typically include: glucose tolerance, insulin tolerance, food intake and body composition. Resource animals, in addition to weight and fat mass gains, develop increased insulin resistance with a small subset of animals continuing to develop co-morbidities identified in humans, such as type 2 diabetes.  

The goals of the Resource are: 

• To understand the timeline for the progression of different aspects of metabolic disease: obesity, diabetes, cardiovascular disease, and immune dysfunction. 
• To supply access to an established colony of DIO NHP for research projects. 
• To generate DIO pre-diabetic NHP according to research needs. 
• To provide planning, oversight and coordination of internal and external obesity-related research projects, including promotion of collaborative efforts. 
• To distribute samples to investigators from our Bio-bank of DIO NHP longitudinal specimens harvested at various stages of obesity. Samples include serum, plasma, and various tissue biopsies. 

For information on tissue or animal availability please contact Kristin Sauter at sauterkr@ohsu.edu.

Technical approaches employed by the Resource: 

Dual energy X-ray analysis (DEXA). The ONPRC has a GE Lunar iDXA scanner for doing body composition analysis with v18 enCORE software capable of advanced measures of metabolic health including CoreScan with separate visceral and subcutaneous tissue measurements.  

Energy expenditure. Double-labeled water analysis is commonly used in humans to measure basal energy expenditure and has been validated in NHPs. This is a non-invasive technique that relies on two forms of labeled water (2H218O and 2H2O) and the utilization of these substrates to generate CO2. The Obese NHP Resource also has access to an Oxymax system from Columbus Instruments to measure indirect calorimetry and energy expenditure. This system was specifically designed for use with NHP. 

Telemetry systems. Telemetry systems that measure blood pressure, heart rate, activity, body temperature, and/or ECG are employed. 

Hyperinsulinemic-euglycemic clamps. While glucose and insulin tolerance tests (both used extensively within the resource) can give an indirect measure of whole-animal insulin resistance, clamp studies are used to detect insulin resistance in peripheral tissues (i.e., muscle and fat). These studies use the infusion of labeled substrates while clamping insulin at high levels and infusing glucose to maintain euglycemia. 

Magnetic resonance spectroscopy (MRS). MRS analysis of ectopic lipid accumulation in the liver and muscle (as well as other tissues). This has become a valuable and powerful technique used in humans to investigate fatty liver disease and the correlation of ectopic lipid accumulation with insulin resistance and the progression to diabetes. 

Contrast-enhanced ultrasound (CEU). This is a technique to measure vascular reactivity and tissue perfusion. This non-invasive perfusion imaging technique relies on the ultrasound detection of microbubble contrast agents during their tissue microvascular transit. Encapsulated microbubble contrast agents that are currently used for CEU imaging are ideal for the assessment of perfusion, since they are inert and remain in the vascular compartment, and their microvascular rheology is similar to that of red blood cells. 

Ex vivo tissue studies. The resource has access to isolated NHP islets for the ex vivo study of glucose-stimulated insulin secretion via the use of a Biorep perifusion system. NHP islets can also be distributed based on availability. Additional access to a Seahorse Xfe24 allows examination of cellular metabolic rates in various cells or adipose tissue biopsies.  

Recent publications involving the Resource: 

Sass F, et al. NK2R control of energy expenditure and feeding to treat metabolic diseases. Nature. 2024 Nov;635(8040):987-1000. doi: 10.1038/s41586-024-08207-0.  

Carroll DT, et al. Preparation of Frozen Non-Human Primate Fetal Islets for Combined Single Nuclei RNA-Sequencing and ATAC-Sequencing, and Bulk Metabolomics. J Vis Exp. 2024 Nov 8;(213). doi: 10.3791/66849. 

Webb GM, et al. Effect of metabolic status on response to SIV infection and antiretroviral therapy in nonhuman primates. JCI Insight. 2024 Aug 8;9(18):e181968. doi: 10.1172/jci.insight.181968.  

Kohs TCL, et al. Activation of coagulation FXI promotes endothelial inflammation and amplifies platelet activation in a nonhuman primate model of hyperlipidemia. Res Pract Thromb Haemost. 2023 Nov 27;8(1):102276. doi: 10.1016/j.rpth.2023.102276.  

Chan-Ling T, et al. Glial, Neuronal, Vascular, Retinal Pigment Epithelium, and Inflammatory Cell Damage in a New Western Diet-Induced Primate Model of Diabetic Retinopathy. Am J Pathol. 2023 Nov;193(11):1789-1808. doi: 10.1016/j.ajpath.2023.02.019.  

Nash MJ, et al. Maternal diet alters long-term innate immune cell memory in fetal and juvenile hematopoietic stem and progenitor cells in nonhuman primate offspring. Cell Rep. 2023 Apr 25;42(4):112393. doi: 10.1016/j.celrep.2023.112393.  

Brown E, et al. Arterial Platelet Adhesion in Atherosclerosis-Prone Arteries of Obese, Insulin-Resistant Nonhuman Primates. J Am Heart Assoc. 2021 May 4;10(9):e019413. doi: 10.1161/JAHA.120.019413.  

Ravisankar S, et al. Short-term Western-style diet negatively impacts reproductive outcomes in primates. JCI Insight. 2021 Feb 22;6(4):e138312. doi: 10.1172/jci.insight.138312.  

Murray SA, et al. Whole transcriptome analysis and validation of metabolic pathways in subcutaneous adipose tissues during FGF21-induced weight loss in non-human primates. Sci Rep. 2020 Apr 29;10(1):7287. doi: 10.1038/s41598-020-64170-6.  

Rangwala SM, et al. A Long-Acting PYY3-36 Analog Mediates Robust Anorectic Efficacy with Minimal Emesis in Nonhuman Primates. Cell Metab. 2019 Apr 2;29(4):837-843.e5. doi: 10.1016/j.cmet.2019.01.017. 

The Infectious Disease NHP Resource (IDR) serves to facilitate a large and diverse portfolio of infectious disease research to develop vaccines and therapies as well as understand pathogenesis for viral, bacterial, and parasitic diseases. Ongoing studies involve a range of pathogens, including SIV/SHIV as models for HIV, hepatitis B, yellow fever virus, Zika virus, chikungunya virus, rhesus rhadinovirus, cytomegalovirus, Mycobacterium tuberculosis, Neisseria gonorrhea, and Plasmodium species (malaria). The IDR supports nonhuman primate research with other pathogens that require ABSL2 and ABSL3-level biocontainment. The IDR supports all aspects of study planning, conduct of specialized technical, surgical, pathological and imaging procedures, optimization and development of new procedures or models to address experimental questions, and interpretation of data. For information on tissue or animal availability please contact Scott Hansen at hansensc@ohsu.edu.

The Precision Medicine NHP Resource (PMR)  provides data on genetic variants in rhesus and Japanese macaques in the ONPRC NHP colonies, helping investigators optimize the animals used in their studies and to identify unique models of genetic diseases. The PMR maintains the macaque genotype and phenotype database (mGAP) of DNA variants that is curated and heavily annotated and can either be viewed through our genome browser or downloaded for external use. 

The PMR also oversees the unique Japanese macaque (JM) captive breeding colony, initially established in 1965 with a gift of 55 animals from the Japanese government. This colony has propagated for more than six decades without the addition of new founders, evolving into a one-of-a-kind NHP resource, and producing unique genetic disease models not available in other NHP species or even other JM colonies. Tissues from each of the following genetic models have been banked and are available to investigators for research purposes. Japanese macaque encephalomyelitis (JME), a disease that recapitulates both the etiological and pathophysiological processes that occur in multiple sclerosis (MS) . To our knowledge, this disease only occurs in the ONPRC JM colony, providing an unprecedented opportunity to study the mechanisms underlying the onset of inflammatory demyelinating disease and providing a platform to test novel MS therapeis.  For more detailed descriptions see: 

• Blair, et al., Immunopathology of Japanese Macaque Encephalomyelitis is Similar to Multiple Sclerosis. J Neuroimmunol. 2016 Feb 15;291:1-10. doi: 10.1016/j.jneuroim.2015.11.026. 
• Axthelm, et al., Japanese Macaque Encephalomyelitis: A Spontaneous Multple-Sclerosis-Like Disease in a Nonhuman Primate. Ann Neurol. 2011 Sep;70(3):362-73. doi: 10.1002/ana.22449. Epub 2011 Jun 14. 

Retinal disease that closely parallel human Dominant Drusen syndromes such as Malattia Leventinese/Doyne honeycomb dystrophy. Long-term studies of this model has provided important insight into the effects of age and diet on retinal disease progression.  For more detailed descriptions see: 

• Pennesi, et al.,2014. Measuring Cone Density in a Japanese Macaque (Macaca fuscata) model of age-related macular degeneration with commercially available adaptive optics.   Adv Exp Med Biol. 2014;801:309-16. doi: 10.1007/978-1-4614-3209-8_39. 

Neuronal ceroid lipofuscinosis (NCL, Batten Disease, CLN7) is also naturally expressed in the JM colony.  Retinal, neural imaging and histological studies have demonstrated the highly parallel nature of JM and human CLN7 disease. For more detailed descriptions see: 

• McBride et al., 2018. Discovery of a CLN7 Model of Batten Disease in a Non-Human Primates Neurobiology of Disease (119) 2018 65-78. doi: 10.1016/j.nbd.2018.07.013. Epub 2018 Jul 23. 

For information on tissue or animal availability please contact Larry Sherman at shermanl@ohsu.edu.