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, challenges remain, as evidenced by the recent pandemic and the susceptibility of the old to novel pathogens.  Moreover, to increase the “healthspan” of retirees, amelioration of fragility and chronic, progressive illnesses is a continued long-term goal.  This situation has a significant social-economic impact, with mandatory federal spending on elderly health care continuing to rise.

Demographic models have long forecast the increase in the aged population, which led to the creation of the National Institute on Aging (NIA) in 1974.  The NIA supports both clinically-based and basic research on the biology of aging and its associated diseases.  Because clinically-based studies are difficult to control, with heterogeneity in genetics, life histories, and exposure to different environments, the NIA makes available more easily controlled animal models for aging research.  Genetically-defined rodent strains are the mainstay of such efforts, but 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, with similar genetics, anatomy, physiology, and is also endowed with a long lifespan compared to rodents.  But, the NIA has also recently added marmosets, as a shorter-lived alternative to longer-lived old-world monkeys in the quest for 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, (eg.- MRI scans).
• Maintain an aged nonhuman primate tissue archive for scientific discovery.
• Explore the ONPRC database for describing aging in the primate model.

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.

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

To develop opportunities for research in the field of nonhuman primate metabolism, Dr. Paul Kievit and his colleagues have established two colonies of macaques that are fed a diet high in saturated fat, simple carbohydrates and cholesterol. These Diet-Induced Obesity (DIO) nonhuman primate (NHP) models are maintained in an effort to understand the progression of obesity and its associated metabolic disorders, as well as to provide a model for treating these disorders. Briefly, the two models are:

1.   DIO Rhesus macaques (Macaca mulatta). These studies involve singly- or group-housed animals that have extensive phenotypic characterization, including glucose tolerance, insulin tolerance, food intake, energy expenditure, activity, and cardiovascular function. These macaques have been used in a variety of studies, including investigation of cardiovascular changes in response to a high-fat diet, as well as pharmaceutical and surgical therapeutics for obesity.

2.   DIO in Cynomolgus macaques (Macaca fascicularis). This cohort of over 30 cynomolgus macaques are maintained on a high-fat/high-calorie diet. These animals can support research models that investigate metabolic disease in NHP. As part of the Obese NHP Resource, these animals have extensive phenotypic characterization, including glucose tolerance, insulin tolerance, body composition, and food intake.

This resource is being expanded for internal and external studies. The primary goals for the Obese NHP Resource are:

• To encourage interdisciplinary, collaborative studies that will specifically lead to additional funding in the various metabolic disease areas. This will be accomplished through interaction with the Division of Cardiometabolic Health.
• To understand the timeline for the progression of the different aspects of the metabolic disease;i.e., obesity, diabetes, cardiovascular disease, and immune dysfunction.
• To determine the characteristics (i.e., genetic and behavioral) that make some animals susceptible to diet induced obesity, while other animals are highly resistant.
• Provide oversight and coordination of all internal and external research projects, including promotion of collaborative efforts.
• Provide investigators with a Bio-bank of harvested samples from animals at various stages of obesity. Samples include serum, plasma, and specific tissue samples collected during the development of obesity.

Technical approaches employed by the Resource:

Magnetic resonance spectroscopy (MRS). The ONPRC has recently obtained a 3T magnet from the main OHSU campus. One of the possible applications of this technology to the Obese NHP resource is through 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.

Dual energy X-ray analysis (DEXA). The ONPRC has a Hologic Discovery A DEXA scanner for doing body composition analysis. This is the same machine used in OHSU clinics. This machine is available through charge-backs ($50 per animal), which covers its maintenance contract and upgrades.

Ex vivo islet culture system. A large-capacity physiological culture system has been recently established that enables the analysis of cells and organelles such as pancreatic islets under conditions that approximate in vivo conditions of CO2, O2, temperature, and 3-dimensional suspension culture. This system is optimized for NHP islets, and includes detailed analysis of islet function utilizing perifusion.

Energy expenditure. Double-labeled water analysis is commonly used in humans (children and adults) to measure basal energy expenditure. This technique has been validated in NHPs as well. This is a non-invasive technique that relies on two forms of labeled water (H218O and 2H2O) and the utilization of these substrates to generate CO2. This is a valuable technique to use in NHPs because it can be performed on large numbers of animals, which makes it ideal for both individually-housed animals as well as group-housed animals. 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 the use of NHP.

Telemetry systems. Telemetry systems that measure blood pressure, heart rate, activity, body temperature, and ECG are employed for individually housed animals, and Actiwatch accelerometers can be used in both single and group-housed animals.

Hyperinsulinemic-euglycemic clamps. This is an important technique for extensive analysis of insulin resistance. While glucose and insulin tolerance tests (both used extensively at ONPRC) 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.

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.

Immune function. Through Pathobiology and VGTI investigators, there is vast array of expertise to study NHP immune function. It is well accepted that obesity and diabetes in humans is associated with immune disorders and inflammation, and that this condition may contribute to the progression of the disease and the pathology.

Paul Kievit, Ph.D., Director
Lindsay Bader, Colony Manager

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 is capable of supporting 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 send an e-mail to: hansensc@ohsu.edu

The Japanese Macaque NHP Resource (JMR) 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. For information on tissue or animal availability please contact Betsy Ferguson at fergusob@ohsu.edu

Japanese macaque encephalomyelitis (JME), a disease that recapitulates both the etiological and pathophysiological processes that occur in multiple sclerosis (MS) and related demyelinating diseases. 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 like MS.  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.