Age-Associated Pathology in Rhesus Macaques (Macaca mulatta)

Abstract

The rhesus macaque (Macaca mulatta) is one of the most extensively used nonhuman primate models for human diseases. This article presents a literature review focusing on major organ systems and age-associated conditions in humans and primates, combined with information from the Wisconsin National Primate Research Center Electronic Health Record database to highlight and contrast age-associated lesions in geriatric rhesus macaques with younger cohorts. Rhesus macaques are excellent models for age-associated conditions, including diabetes, osteoarthritis, endometriosis, visual accommodation, hypertension, osteoporosis, and amyloidosis. Adenocarcinoma of the large intestine (ileocecocolic junction, cecum, and colon) is the most common spontaneous neoplasm in the rhesus macaque. A combination of cross-sectional and longitudinal studies is required to truly define mechanisms of maturation, aging, and the pathology of age-associated conditions in macaques and thus humans. The rhesus macaque is and will continue to be an appropriate and valuable model for investigation of the mechanisms and treatment of age-associated diseases.

Keywords: Macaca mulatta; aging; amyloid; cross-sectional studies; diabetes; disease prevalence; diverticulosis; endometriosis; neoplasia; rhesus macaque.

Figure 1

Aged rhesus macaque. There is thinned dermis and pelage with diminished muscle mass, a prominent stifle joint, and severe kyphosis. Photo by Jennifer Coonen. Figures 2–4. Intimal fibrous plaques, abdominal aorta, rhesus macaque. There are multiple segmental intimal fibrous plaques and (Fig. 4) focal mineralization of an intimal plaque. Hematoxylin and eosin. Figure 5. Endocarditis, left atrioventricular valve, rhesus macaque. A reddened rough-surfaced vegetative lesion (arrow) affects the valve leaflet.

Figure 6, 7

Valvular endocardiosis, left atrioventricular valve, rhesus macaque. Figure 6. There is multifocal smooth nodular thickening of valve leaflets (arrows). Figure 7. There is mild nodular proliferation of mucinous to fibrous tissue within the valve leaflet. Hematoxylin and eosin (HE). Figures 8, 9. Heart, left ventricle, rhesus macaque. Figure 8. There is focal interstitial fibrosis (*), individual myocardiocyte hypertrophy (arrows), and multifocal adipocyte infiltration. HE. Figure 9. There is interstitial fibrosis dissecting between myocardiocytes. Masson trichrome. Figures 10, 11. Pulmonary acariasis (Pneumonyssus simicola), lung, rhesus macaque. Figure 10. There are numerous pale parasitic cysts in all lung lobes. Image by Andres F. Mejia. Figure 11. Pneumonyssus mite (arrow) within a bronchiole with marked focal bronchiolar inflammation. HE.

Figure 12

Pulmonary acariasis (Pneumonyssus simicola), lung, rhesus macaque. The mite has with legs covered by chitinous exoskeleton (arrows), striated muscle (*), digestive tract (D), and yolk glands (Y). Inflammation surrounding the mite consists of a multinucleate giant cell (arrowhead), lymphocytes, plasma cells, macrophages (inset), and eosinophils (inset). Hematoxylin and eosin. Figure 13. Subpleural bullae, lung, rhesus macaque. Multiple clear bullae are scattered throughout several lung lobes. Figures 14, 15. Kyphosis, thoracic vertebrae, rhesus macaque. Figure 14. Severe thoracic kyphosis with an approximately 90-degree deviation in this animal’s spine. Figure 15. Thoracic kyphosis is more evident with removal of the skin.

Figure 16

Spondylosis, thoracic vertebrae, rhesus macaque. There is severe osteoarthritis and bridging spondylosis on the pleural (anterior) aspects of multiple vertebrae. Figures 17, 18. Osteoarthritis, femurs, rhesus macaque. Figure 17. There is multifocal degeneration, eburnation and focal erosion of cartilage, and central and peripheral osteophyte formation on both distal femoral condyles. Figure 18. There are multiple severe irregular cartilaginous erosions. Figure 19. Mature cataract, lens, rhesus macaque. There is separation of lens fibers and Morgagnian globule formation. Hematoxylin and eosin (HE). Figures 20, 21. Chronic interstitial nephritis, kidney, rhesus macaque. HE. Figure 20. There is lymphocytic inflammation and interstitial fibrosis with fibrous thickening of Bowman capsule (arrows) with hypertrophy of parietal epithelium. Figure 21. There is a sclerotic glomerulus (S) with an adjacent atrophied tubule surrounded by lymphocytic interstitial inflammation and interstitial fibrosis. An ectatic tubule (T) is at the margin of the section. HE

Figures 22, 23

Endometriosis, abdominal cavity, rhesus macaque. Figure 22. There are multiple small foci of endometriosis (arrows) within the omentum. Figure 23. An ovary with focal endometriosis (E) surrounded by stromal decidualization (D), an antral follicle (A), and multiple primordial follicles (arrowheads). Hematoxylin and eosin (HE). Figures 24-27. Endometriosis, uterus, rhesus macaque treated with medroxy-progesterone acetate. Figure 24. Proliferative endometrial tissue (arrow) protruding through the cervix (*) into the vagina with adherent fibrinonecrotic exudate. Figure 25. A longitudinal section of the uterus, cervix (*), and proximal vagina with markedly proliferative endometrium and polypoid endometrial tissue (arrow) projecting through the cervix into the vagina. Figure 26. There are irregular endometrial glands (G) and marked proliferation of decidualized secretory stroma (S). HE. Figure 27. Higher magnification of gland (G) and stroma (S). HE.

Figure 28

Amyloid, pancreas, rhesusmacaque. Three pancreatic islets are expanded and effaced by amyloid. Hematoxylin and eosin (HE). Figures 29, 30. Amyloid, liver, rhesus macaque. Figure 29. There is severemultifocal amyloidosis of liver lobemargins. Figure 30. Amyloid-markedly expands the spaces of Dissewith compression and atrophy of hepatocytes. HE. Figures 31, 32. Diverticulosis, colon, rhesusmacaque. Figure 31. There are numerous variably sized diverticula. Photo byAmy Usborne. Figure 32. Mucosal surface with multiple fecaliths composedof ingesta andhairwithindiverticula. Photo by Amy Usborne. Figure 33. Diverticulosis, colon, rhesus macaque. The submucosa of the diverticulum directly abuts the mesenteric adipose tissue and is lined by mildly inflamed mucosa with muscularis mucosae (*) present only at the margin of the section. HE.

Figure 34

Polyp with adenocarcinoma, ileocecal junction, rhesus macaque. Hematoxylin and eosin (HE). The polyp has a central fibrous core, and irregularly shaped and sized neoplastic glands surrounded by variable lymphoplasmacytic inflammation (inset) expand the mucosa with focal intraglandular hemorrhage and mucosal ulceration. Figures 35, 36. Adenocarcinoma, cecocolic junction, rhesus macaque. Figure 35. There is an ulcerated circumferential adenocarcinoma (arrow) with luminal constriction, severe ileocecal ectasia, and prominence of the ileocecal valve (arrowheads). Figure 36. Irregularly sized and shaped neoplastic glands expanding and effacing the mucosa, submucosa, and inner muscular layer with a discontinuous muscularis mucosae (arrow) and nodular lymphoid hyperplasia (arrowheads). HE. Figures 37-39. Paraneoplastic syndrome, rhesus macaque. Figure 37. There is bilaterally symmetrical cutaneous hyperkeratosis. Photo by Christina Cruzen. Figure 38. An axillary lymph node is effaced by a metastatic neoplasm composed of ribbons and packets of neoplastic cells supported by fine fibrovascular stroma. HE. Figure 39. Primary pancreatic endocrine neoplasm composed of cuboidal cells forming nests, packets, and acini with fine fibrovascular stroma surrounded by a dense fibrous capsule (arrowheads) and exocrine pancreas (P). HE.