Comparative Pathology of Aging Great Apes

Hair Loss and Graying

Can one tell from outward appearances if an ape is old? Balding or thinning hair and gray hair are commonly associated with aging in humans. In wild chimpanzees, characteristics used to identify older females include dull, thin, brownish, or graying hair coat with thinning most marked on head, shoulders, and back; tooth loss; sagging, wrinkled faces; and slower, more deliberate movement. ^24,118,179 Hair loss in nonhuman primates may be due to parasitism, atopy, self-plucking (trichotillomania), or excessive allogrooming and by itself should not be assumed to be age related. ^34,187 Gorilla adult males develop silvering of the hair in a saddle pattern on the back and upper limbs (extending more distally in western lowland gorillas) at about 13 y, but this does not necessarily increase with age.

Frailty and Sarcopenia

Frailty is a phenotype of aging humans and is defined as having ≥3 of the following 5 signs: slowness of gait, loss of hand grip strength, self-reported exhaustion, low energy levels, and unintended weight loss. ⁵¹ Frailty is often accompanied by sarcopenia, which is defined as loss of muscle mass, strength, and quality, principally as a result of old age (but also occurring in disease-associated cachexia). ^7,47 Sarcopenia is defined histologically by decline in the number and size of myofibers, especially type II fast-twitch fibers, and by fatty infiltration of muscles (steatosis). It is thought to be due to a complex interplay of nutrition, decreased exercise, decreased anabolic hormones, increased oxidative damage, abnormal mitochondrial function, and altered autophagy and myostatin-dependent signaling. ²¹⁷ It is not known if frailty and sarcopenia occur in elderly apes. Studies of wild and captive chimpanzees have noted decreased or slow locomotion in older animals, which was attributed to arthritis. ²⁴ The few necropsied wild chimpanzees at Gombe with clinical histories of frailty and histologic evidence of sarcopenia have had underlying infections, commonly chimpanzee simian immunodeficiency virus (SIVcpz) with AIDS-like immunopathology. ²⁵³ Trackers for the wild mountain gorillas have noted that geriatric animals often move more slowly and are separated from their groups. Generalized wasting is also seen; usually, this is associated with specific lesions at necropsy, such as infections, traumatic wounds, and fractures (L.J.L., Gorilla Doctors, unpublished data). Of the elderly zoo apes that we examined postmortem, most had impressive retention of muscle mass and tone despite chronic debilitating conditions. Therefore, establishing whether old age–related frailty exists in apes, in the absence of non-age-related comorbidities, requires further research.

Types of Nonseptic Arthritis

Arthritis increases with age in all species examined to date. It is estimated that over half of human adults >65 yo have joint pain and/or overt arthritis. ^149,286 Sorting out the comparative aspects of arthritis can be difficult because of confusing and changeable nomenclature and probable differences among species. ^3,54,211 In humans and domestic species, refining the diagnoses of arthritis relies on clinical symptoms and laboratory tests, along with imaging studies (radiography and magnetic resonance imaging [MRI]), joint effusion cytology, and, occasionally, synovial biopsy.

The most common type of old age, “wear and tear” arthritis is often called degenerative joint disease (DJD), a term used interchangeably with osteoarthritis and osteoarthrosis (OA). ²²⁸ The term osteoarthritis implies that inflammation is present, while osteoarthrosis is a broader term. Which term is used often depends on the user’s bias or understanding of pathogenesis. OA is not an inevitable result of human aging but likely occurs due to accumulated insults and predisposing factors, such as obesity, female sex, genetic/racial background, macrotrauma (eg, sports injuries), and underlying problems with joint mechanics (eg, angular deformity, laxity, or dysplasia). ^228,286 These lead to mechanical microtrauma and resulting damage to cartilage, joint capsule, supporting tendons and ligaments, and subchondral microvasculature. Although inflammation can occur as a result of degradation of joint components by mechanical forces, this is not primarily an inflammatory arthritis (IA), although some recent literature contests this. ²⁸⁴ Articular cartilage has little potential for spontaneous repair even in younger individuals, and, as in all organ systems, repair mechanisms and cellular and matrical plasticity decrease with age. ²²⁰ The term chondrosenescence has been coined to highlight the changes. ¹⁷³

In contrast, IA can begin at any age, although disability is marked in the elderly. Two main types of IA in humans include (1) autoimmune erosive rheumatoid arthritis (RA), in which patients’ serum is positive for rheumatoid factor, and (2) “seronegative,” “nonerosive,” or “reactive” arthritis, which is secondary to inflammatory processes elsewhere in the body (eg, inflammatory bowel disease, bacterial enteritis, urinary tract infections, psoriasis). ^30,226 Some authors consider seronegative arthritis in humans to be an erosive disease, which confuses the nomenclature further. ²¹¹ The presence of predisposing disease processes is a major criterion for a clinical diagnosis of IA. Since seronegative arthritis often involves the spine, the term spondyloarthropathy (SA) has been used by some authors to refer collectively to these inflammatory syndromes. ^210,211 Humans with SA commonly but not invariably carry the major histocompatibility complex class I allele HLA B27. ²²⁶

Diffuse idiopathic skeletal hyperostosis (DISH) is a symptomatic or asymptomatic disease of the spine and entheses of peripheral joints, especially in elderly men. ¹⁸² There is confusion in the literature about when to apply this term and how to differentiate it from other forms of spinal arthritis with bony proliferation. Criteria have been used to differentiate DISH from OA and SA—such as anterior vertebral body fusion/bridging in areas of intact disc space, absence of sacroiliac disease, and calcification peripheral to the joints. A review of degenerative skeletal diseases of primates stated that DISH is likely underdiagnosed in nonhuman primates and that nonhuman primate spinal lesions have been commonly, possibly erroneously, lumped under degenerative disc disease. ³

Another type of arthritis that occurs in older humans is crystal deposition disease, which includes deposition of uric acid crystals (ie, articular gout) or calcium pyrophosphate deposition (CPPD; pseudogout). ¹⁵¹ Among primates, gout appears to be a uniquely human malady. CPPD, however, has been reported in a variety of nonhuman primates. ²⁰⁴ Both conditions are increased in older and elderly humans, with a mean age of 69 y for gout and 73 y for CPPD. ¹⁵¹ Men are more affected than women (82% of gout cases, 63% of CPPD). CPPD can present as a primary acute mono- or pauciarticular IA, but calcium pyrophosphate crystals are also common in joints affected by OA, IA, infections, and joint instability. ^1,209 Mechanical compression of cartilage causes shedding of crystalline CPP into the joint; the crystals then cause an inflammatory reaction that must be differentiated from immune-mediated IA. ¹⁰⁸

There is overlap in the distribution of joint involvement in the types of arthritis. DJD/OA in humans involves ≥1 joints and is usually asymmetrical. The most affected joints are those of hands, knees, hips, and shoulders. DJD/OA can also involve the articular facets of the spine (ie, apophysial or zygapophyseal joints) and the vertebral bodies, especially in the neck and lumbar spine in humans. ²¹ It is often associated with disc space collapse due to the age-related desiccation of the nucleus pulposus, termed degenerative disk disease (DDD). Spinal OA secondary to DDD can lead to osteophytic “lipping” or complete bridging between vertebral bodies (“spondylosis”) and osteophytosis of apophyseal joints. ²¹ DISH begins as ossification of the ventral ligaments and tendons of the lumbar and cervical spine (enthesophytosis) and can lead to bridging and fusion of vertebral bodies. ³ DISH is not predisposed to by DDD. Spondyloarthropathy/IA also causes bridging and fusion of vertebral bodies due to formation of syndesmophytes. Sacroiliac joint fusion is commonly present as well, with or without involvement of ≥1 joints of the appendicular skeleton (generally <5; ie, pauciarticular). ²¹⁰ Ankylosing spondylitis is a subtype of SA in which the combination of damage to intervertebral joints and fusion of vertebral bodies is the main phenotype. ²¹⁵ In RA, there is symmetrical distribution, involving >5 joints, often beginning in distal “small joints” (eg, wrists, ankles, hands, and feet). CPPD can involve any joint but is usually in the appendicular skeleton, and it can occur concurrently in joints affected by OA and SA. ²⁰⁹

Morphologically, DJD/OA is differentiated from SA, particularly in synovial joints, by sclerosis rather than erosion of the subchondral plate. ²¹¹ Cartilage changes in OA include grooving (score lines), pitting, and focal or diffuse full-thickness loss of articular cartilage with eburnation of underlying exposed bone. In SA, erosions are primarily marginal, and there is often adjacent new bone formation in response to the erosions. In OA, there is often remodeling of articular surface contours with osteophyte production at the junction between articular cartilage and bone. The latter is in contrast to the mineralization and bone formation in the joint capsule insertions and attached ligaments and tendons (ie, entheseal bone formation, enthesophytes) that occur in SA. DISH also causes ligamentous enthesophyte formation but begins in the ventral spinous ligament, whereas the bone formation in SA usually involves only the margins of the annulus fibrosis (ie, syndesmophytosis). ¹⁸² Radiographically, “flowing” calcification causing fusion of vertebral bodies and calcification of ligaments of the paraspinous processes is more suggestive of DISH. ³ Confusingly, bone proliferation in SA can also cause vertebral body bridging (due to syndesmophytosis) and fusion of the articular facets (due to apophyseal enthesophytosis). In CPPD, crystalline material can be seen grossly coating or embedded in cartilage or soft tissues of synovial (diarthrodial) joints.

Arthritis in Wild Apes

Most information in the literature on arthritis in ape species comes from studies of museum collections of defleshed skeletons from wild apes killed in the early part of the 20th century and exhumed skeletal remains of apes from long-term field studies, such as those initiated by Jane Goodall (chimpanzees) and Dian Fossey (mountain gorillas). Classification of the type of arthritis from these specimens is problematic, since helpful soft tissue changes, clinical laboratory data, and postmortem diagnosis of concurrent diseases that support or refute the diagnosis of IA are typically lacking. Lesions in such specimens often represent “end stage” arthritis and may have characteristics of different processes. Additionally, in most cases, the exact age at death is unknown, and few of the skeletons are likely to have come from truly geriatric individuals. Comparison among studies is further complicated by the use of varying methodologies and terminologies (see above).

By examining museum collection skeletal remains of wild adult bonobos and 2 subspecies of common chimpanzee (P. troglodytes troglodytes, the “central” chimpanzee; P. t. schweinfurthii, the “eastern” chimpanzee), the authors of 1 study concluded that SA, rather than OA, was the predominant type of arthritis in chimpanzees. ²¹³ OA was found in 1 of 34 (3%) bonobos and 6 of 79 (7.5%) central and 1 of 26 (3.8%) eastern chimpanzees, while SA was seen in 21% of bonobos and 28% of both chimpanzee subspecies. In animals characterized as having SA, sacroiliac involvement was present in 100% of bonobos, 71% of eastern chimps, and 18% of central chimps. In contrast, another study of wild African ape skeletons—including eastern chimpanzees (from Gombe, Tanzania), central chimpanzees, bonobos, and lowland gorillas (from museum collections)—found only rare spinal lesions (confusingly designated “vertebral osteophyte production” if involving the vertebral bodies and OA if involving the articular facets). ¹³⁰ OA of peripheral joints was also rare. OA of the shoulder joints was seen in only 2 elderly bonobos, and unilateral knee OA was present in 1 bonobo. Two more recent studies investigated remains of age-known chimpanzees in Kibale National Park in Uganda and Gombe National Park in Tanzania using the same methodology.^44,136 In both these studies, degenerative joint lesions were more common in the appendicular skeleton than spine, although in the Gombe chimps the lumbosacral spine was affected in some animals. At Kibale, lesions were noted in 75% of individuals. Except for 2 old females, cases of severe arthritis were associated with evidence of past trauma. ⁴⁴ At Gombe, OA was positively correlated with age such that 84% of chimpanzees >15 y of age had moderate or severe OA. Arthropathy was most common in the elbow, hip, and knee joints. ¹³⁶

Arthritis is found in wild gorillas, and evidence of SA was more prevalent than OA in adult skeletons from both western lowland gorillas and eastern gorillas (mountain and Grauer’s subspecies were lumped together). ^212,216 OA was found in 1 of 38 (3%) eastern gorillas and 8 of 99 (8%) western gorillas, while SA was seen in 8 of 38 (21%) eastern gorillas and 20 of 99 (20%) western lowland gorillas. SA was male predominant. ²¹² Another study agreed that joint disease was most often spinal in mountain gorillas, mostly in lumbar spine. ¹⁵³

In a study examining 55 adult orangutan skeletons from museum collections (identified as the Bornean orangutan, Pongo pygmaeus pygmaeus), 89% of specimens were from wild animals. ²¹⁴ No evidence of OA was found, but 11% had hallmarks of inflammatory or erosive arthritis (9% males and 15% females). The authors concluded that the pattern in orangutans was similar to that of other great apes (“which clearly have spondyloarthropathy”), except for involvement of statistically fewer metacarpal phalangeal joints, the complete absence of new bone growth at margins of erosions, and a trend toward less sacroiliac joint involvement.

Arthritis in Captive Apes

OA can be classified as primary (when no underlying condition is identified) or secondary (with previous trauma the most common predisposition in humans). ⁹⁰ Wild apes often show evidence of concurrent trauma, complicating subclassification. In contrast, trauma is less common in captive apes, but other risk factors may contribute to their arthritis (exhibit design, obesity, etc). In our experience, common sites include the knees, hips, elbows, and lower spine.

The literature contains a case report of clinically diagnosed bilateral knee DJD/OA in a 25 yo male laboratory-housed chimpanzee and a report in which 3 geriatric chimpanzees (2 males 40 and 45 yo and a female 40 yo) were treated with acupuncture for OA of the knees (stifle joints). ^158,266 No published reports on arthritis in captive bonobos were found, and the only case in the Bonobo SSP pathology database with a diagnosis of arthritis was a 54 yo female with severe OA of the right hip and mild degenerative changes in the right knee; she died of cardiomyopathy. Since the next-oldest animals in the database are only in their 30s, it may be that OA is a late life event in this species.

The prevalence of arthritis in the SSP population of gorillas (deceased and still living) has not been determined. Initial reports of “rheumatoid arthritis” in several infant to young adult gorillas were associated with intra-articular mycoplasma infection and lymphoplasmacytic synovitis. ⁴⁰ However, the described asymmetrical pattern of joint involvement is more suggestive of either septic or reactive arthritis rather than true RA. ²¹² It is unknown if these gorillas suffered clinically from arthritis as they aged. Several additional reports of appendicular and spinal arthritis, dating back to the 18th century, suggest that both DJD and OA are present in old gorillas. ³⁵ A 33 yo male gorilla was euthanized because of severe bilateral OA of the hips. ¹⁶ A study of skeletons from 3 male (36, 36, 37 yo) and 2 female (23–25, 27 yo) zoo-housed lowland gorillas found slight changes of “lipping” in only 8% of forelimb joints but severe changes in 25% of the lower limb joints, with the males more affected. ¹⁸⁴ “Lipping” of vertebral “centra” (bodies) was present in 70% of vertebrae in males and 68% in females. Although changes were present in cervical, thoracic, and lumbar vertebrae, all affected animals (males and females) had lesions in lumbar vertebrae, and there was fusion of lumbar vertebrae (spondylosis) in all the males.

Two case reports in older adult female gorillas also highlight spinal changes. Traumatic herniation of a lumbar disc necessitating diskectomy was reported in a 36 yo female zoo-housed eastern lowland gorilla (erroneously called a mountain gorilla). ¹⁵ Similarly, a 42 yo female gorilla from another zoo developed spinal stenosis requiring laminectomy. ²⁸² Radiographs in both these papers show abundant syndesmophytes and early vertebral body bridging and, in the case of the first animal, unilateral partial fusion of the sacroiliac joint, all suggestive of SA.

Additional reports suggesting SA in gorillas include an adult female gorilla who developed spinal lesions resembling ankylosing spondylitis and peripheral arthritis when she was 26 yo and underwent bilateral hip replacement. ^2,192 OA was present in spine and other joints when she died at 47 yo (Gorilla SSP data). Her son developed acute IA of the wrist. ² Another adult female (27 yo) developed acute IA postpartum. ¹²³ Three cases of acute peripheral arthritis resembling reactive arthritis have been diagnosed in juvenile gorillas following shigellosis.^183,200 Whether these animals develop more severe degenerative changes as they age remains to be seen. These cases prompted examination of gorillas for a major histocompatibility complex class I marker similar to HLA B27, which predisposes humans to ankylosing spondylitis and other spondyloarthopathies. ^2,123,256 Leukocytes from several gorillas examined clinically via human diagnostic reagents were reactive for HLA B27. ² More sophisticated studies of gorilla leukocyte antigens determined that a class one allele identical to HLA B27 does not exist in gorillas. ²⁵⁸ However, molecular reconstruction of a gorilla class one protein, GoGo-B01, showed binding domains similar to HLA B27, and functional studies showed the ability of GoGo-B01 to bind proteins bound by HLA B27. The role of GoGo-B01 in IA in gorillas needs further investigation, as both affected and unaffected gorillas have this allele.

We could find no published accounts highlighting arthritis in zoo orangutans, but images of a radiograph and a 3-dimensional reconstruction from the spine of an orangutan (age not given) were used to illustrate DISH in a review chapter on skeletal diseases of primates. ³ In contrast to the literature, in our experience, arthritis is common in older adult orangutans. In our cases, the pattern has been confusing, sometimes more suggestive of OA than IA, with eburnation as well as erosion of cartilage and with osteophytes as well as enthesophytes. Spinal involvement has had features of SA and DISH as well as DDD and OA. Severe arthritis of the knees was seen in Sumatran orangutan males 34 and 41 yo (Fig. 1) but not in a 28 yo Sumatran orangutan male who had spinal arthritis with osteophytes, syndesmophytes, and partial fusion in the lumbar spine (Fig. 2) or a 39 yo male Sumatran orangutan who had only OA of the right elbow. A 56 yo Sumatran orangutan female (maximum SSP captive life span record) had arthritis in nearly every joint: the left shoulder, both sternoclavicular joints, both elbows, the right carpus, both knees, and both tarsal joints with a pattern most suggestive of OA (Fig. 3). She also had DDD, dorsal disc protrusions throughout the spine, and some ventral syndesmophytosis, especially in the lumbar area. Interestingly, crystals—confirmed to be calcium pyrophosphate by polarized microscopy as well as hydroxyapatite by chemical analysis (courtesy of Dr Bruce Rothschild, University of Kansas School of Medicine)—were seen in the arthritic left shoulder and the elbows (Fig. 4). This is the only case of CPPD in any of the apes of which we are aware.

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Figure 1. Chronic arthritis, lateral condyle of distal femur, 33-year-old male orangutan. There is marked osteophyte production and thickening of joint capsule with villous synovial proliferation. (University of California Davis William R. Pritchard Veterinary Medical Teaching Hospital [UC Davis VMTH] archives). Figure 2. Chronic spondylosis, lumbar spine, 34-year-old male orangutan. Fusion of lumbar vertebral bodies and articular facet joints is present in this defleshed, bleach-treated specimen. (UC Davis VMTH archives). Figure 3. Chronic arthritis, distal femur, 46-year-old female orangutan. There is severe loss of articular cartilage, with scoring and eburnation of exposed bone, osteophyte “lipping,” and synovial proliferation. (UC Davis VMTH archives). Figure 4. Chronic arthritis with deposition of calcium pyrophosphate crystals, elbow joint trochlear notch of ulna, 46-year-old female orangutan. Some of the gritty white crystals could be easily removed, while others were embedded within the articular surface and thickened synovium. (UC Davis VMTH archives). Figure 5. Severe dental attrition, gingival recession, and tooth loss; anterior view, oral cavity, 48-year-old female chimpanzee. (UC Davis VMTH archives). Figure 6. Severe periodontitis, anterior view of oral cavity, geriatric female orangutan. In addition, there is severe plaque accumulation, gingival recession, and tooth migration. (Courtesy of Dr L. D. Braswell).

In summary, while arthritis seems to be common in captive apes, a more thorough retrospective analysis of pathology reports, clinical histories, and radiographic findings from the SSP populations of known-aged apes is clearly needed to better categorize the type of arthritis and determine prevalence and epidemiology. Prospectively, more detailed examination of all joints at necropsy or during physical examinations of wild and captive apes would also facilitate understanding patterns of arthritis in aging apes.

Female Reproductive Senescence and Menopause

A long period of life after reproductive senescence and menopause seems to be fairly unique to humans among the primates. ^{6,70,72,112,115,272} In wild chimpanzees, reproductive senescence occurs only near the end of life. ⁷⁰ While only a small percentage of wild female chimpanzees live past 40 y, more than half of those gave birth to at least 1 offspring. The oldest known-aged individual giving birth was 55 yo. Some studies of captive chimpanzees provide data that support late-in-life menopause, with menstrual cycles in females as old as 50 yo.^112,115,138 In contrast, other studies of captive chimpanzees found hormonal profiles and interbirth interval patterns suggesting that reproduction may terminate well before death, possibly due to greater longevity than that of their wild counterparts. ⁹⁷ Intervals between menstrual cycles were reported to increase with age between 19 and 39 yo, in a pattern suggestive of perimenopause. ⁹² Changes in reproductive hormones indicative of perimenopause (at 30–35 yo) and menopause (35–40+ yo) have also been recorded. ^261,262 Hormone profiles in one >40 yo bonobo suggested that menopause had occurred in that individual, and histology of her ovaries revealed depletion of primary oocytes and developing follicles, as well as increased connective tissue. ⁹⁷

Data from zoo-housed gorillas in North America suggest that menopause does occur and that it is preceded by a period of irregular cycling and low fertility similar to human perimenopause. ^{17 , 160} Reproductive senescence has been less well studied in the other ape species. In wild mountain gorillas, one 42 yo female was pregnant with a near-term fetus when she was found dead with lesions suggestive of right-sided heart failure (L.J.L., Gorilla Doctors, unpublished). Similarly, female orangutans seem to be able to reproduce to the end of their life spans. ²³³ Note that gynecologic or pathologic evaluation of the reproductive tracts of the senescent female apes is absent from these studies. Pathologic changes resulting in infertility might give a false impression if senescence is defined only by the absence of births. Given the importance of human menopause in determining other age-related health conditions, further investigation is needed into fertility and hormonal changes in aging apes, especially those in zoo and the wild. ^13,104

Female Reproductive Tract Lesions

Morphologic correlates of female reproductive senescence include diminution of ovarian primary oocyte numbers and accumulation of proliferative lesions such as endometrial polyps, endometrial hyperplasia, adenomyosis, uterine neoplasms (eg, fibroids [leiomyomas], and endometrial cancers). ^18,91,98 Depletion of primary oocytes has been clearly demonstrated in histology of old chimpanzees and older female mountain gorillas, although a 31 yo female still had abundant primary oocytes (L.J.L., Gorilla Doctors, unpublished). ¹¹⁵

Adenomyosis has been reported in 2 chimpanzees 32 and 41 yo and in a 48 yo orangutan. ^26,100 Adenomyosis was diagnosed in a 31 yo mountain gorilla with a history of repeated abortions (L.J.L., Gorilla Doctors, unpublished). Endometriosis was diagnosed in a nulliparous 28 yo gorilla with abdominal effusion who died under anesthesia. ⁶⁵ Endometrial polyp formation with infarction and adenomyosis were associated with persistent vaginal bleeding in a 24 yo orangutan examined by one of the authors (L.J.L.).

Reproductive tract tumors, especially leiomyomas (analogous to “fibroids” of women), are reported to occur in 28% of female laboratory-housed chimpanzees.^39,109,267 Increasing age (>30 y) was associated with increased prevalence. Ovarian neoplasms in chimpanzees include “fibrothecomas” in 2 animals, 39 and 48 yo. ⁹⁷ A comprehensive look at the disease of the reproductive tracts of aging chimpanzees is covered in this issue of Veterinary Pathology. ⁴⁸

Leiomyomas have been infrequently reported in other apes, with a single report in a captive lowland gorilla and none in the mountain gorilla pathology database. ¹⁸¹ The Contraceptive Reproductive Health Surveillance program of the Association of Zoos and Aquariums’ Wildlife Contraception Center has found leiomyomas in 1 of 9 gorillas, 3 of 7 Sumatran orangutans, and 0 of 6 Bornean orangutans in addition to 4 of 10 chimpanzees whose reproductive tracts were examined (Dr Anneke Moresco, personal communication)

Malignancies of the female reproductive tract are infrequent in chimpanzees; a recent review found only 3. ⁴⁰ However, there are reports in the literature of cervical, uterine, and ovarian adenocarcinomas in captive lowland gorillas. ^122,191,242 Affected individuals were 35, 36, 39, and 50 yo. A 46 yo western lowland gorilla had a uterine leiomyosarcoma causing urine stasis, pyelonephritis, and fatal sepsis. ⁴²

Male Reproductive Senescence and Reproductive Tract Lesions

Male reproductive senescence (“andropause”) and lesions of the aging human male reproductive tract have been less well studied. New evidence from studies of “primitive” societies suggests that postreproductive longevity happens in men as well as women. ^218,268 Hypogonadism and lower levels of androgens can contribute to relative loss of muscle mass (sarcopenia), osteopenia, and other aspects of a geriatric phenotype. ²¹⁸ Human testicular atrophy is associated with decreased number and volume of Leydig (interstitial) cells. ²⁷ Testicular atrophy due to age alone may be difficult to assess because of the presence of other disease conditions and ill health, which could influence testosterone levels and decrease spermatogenesis.

Among cases that we examined, testicular atrophy and hypospermatogenesis were noted in a 56 yo male zoo-housed chimpanzee with chronic heart failure and two 33 yo Sumatran orangutans, one with acute cholecystitis and heart failure and the other with chronic laryngeal air sacculitis and pneumonia. Adult male gorillas normally have relatively small testes with apparent hypospermatogenesis, but they also have increased interstitial cells, as opposed to the decrease noted in adult men. ^71,81,110 This situation may be normal and cyclic, and although it is commonly seen in older male mountain gorillas, it is difficult to attribute to aging alone.

Testicular tumors in humans, especially seminomas, are not necessarily associated with advancing age, although other types of tumor may be. A mixed Sertoli-Leydig tumor was reported in a 38 yo chimpanzee, and interstitial cell adenomas were reported in a 33 yo gorilla. ^99,129

Benign prostatic hyperplasia, a bane of human males as they age, is reported to develop in “late middle age” (25–29 y) in chimpanzees. ²³⁹ Benign prostatic hyperplasia has not yet been reported in the other apes, perhaps because accessory sex glands are not always examined postmortem.

Heart Disease in Apes Compared With Humans

Heart disease is the leading cause of death in older humans in the United States, accounting for about 25% of all deaths in individuals >64 yo. ¹¹⁷ Based on reviews of the SSP populations and laboratory colonies, cardiovascular disease is also the leading cause of death in captive great apes: 45% of bonobos (SSP data), 41% of gorillas, 38% of zoo chimpanzees, >50% of colony chimpanzees, and 20% of orangutans.* The prevalence of cardiovascular disease increases with age in apes as in humans, although death can occur in nongeriatric adults.

One of the major causes of heart disease in older humans is atherosclerotic coronary arterial disease (CAD) with subsequent cardiac ischemia or infarction causing sudden death or congestive heart failure. ²³⁰ In contrast, in all the apes, an idiopathic condition variously termed fibrosing cardiomyopathy, interstitial myocardial fibrosis, or idiopathic cardiomyopathy is the most commonly diagnosed entity. ^{142,168,220,260} This condition resembles idiopathic myocardial fibrosis in humans, which occurs in the absence of arterial obstruction and has been recognized and debated about for decades. ²²² It also resembles the lesions of human idiopathic cardiomyopathy, hypertensive cardiomyopathy, and experimentally induced catecholamine cardiomyopathy in rhesus macaques. ^93,133,229 Sudden deaths (hypothesized to be due to arrhythmias associated with conduction system fibrosis) and congestive heart failure both occur in affected apes. ^144,168,171 In contrast to CAD, the vessels, primarily endomyocardial (intrinsic) arteries and arterioles, in affected great apes have varying degrees of median hypertrophy and hyalinization (arteriosclerosis and arteriolosclerosis; Figs. 11, 12). However, especially in chimpanzees, fibrosis can occur without detected arterial changes. ^142,253,260 Gross and microscopic changes in the hearts of aging apes are similar to “baseline” aging, but those with cardiac deaths often have exaggerated changes, especially left ventricular hypertrophy, interstitial fibrosis, and polyploidy. Polyploid nuclei in the apes (and Old World monkeys) are often convoluted, in contrast to the “box car” nuclei described in humans. ²²⁹

Cardiac disease increases with age in apes. In gorillas, echocardiography revealed increasing left ventricular wall thickness from 1.6 cm in young adult males to >2.1 cm in males >31 yo, while left ventricular chamber size decreased. ¹⁸⁰ In that study, female gorillas showed little difference in cardiac measurements with advancing age, with left ventricular wall thickness ranging from a minimum of 0.9 cm to a maximum of 1.4 cm. All of the males between 31 and 40 yo in the study were considered to have cardiomyopathy. Increased body weight/obesity correlated with cardiomyopathy. Although males are more often affected, our postmortem examination of hearts showed that females may also develop marked myocardial fibrosis, even in the absence of left ventricular hypertrophy.

Echocardiography of normal adult chimpanzees comparing animals of different ages (10–49 yo) did not find significant differences in left ventricular wall thickness of either males or females with age. ²³⁴ However, left ventricular hypertrophy is seen in some but not all chimpanzees with myocardial fibrosis (Figs. 13, 14). ¹⁴²

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Figures 11 and 12. Vascular lesions in small intramuscular (intrinsic) coronary arteries in a 47-year-old male lowland gorilla with biventricular hypertrophy, “fibrosing cardiomyopathy,” and aortic valve disease. Figure 11. Segmental medial muscular hypertrophy in an area with minimal interstitial fibrosis and marked myofiber hypertrophy indicated by karyomegaly (polyploidy). Hematoxylin and eosin. Figure 12. Hyaline arteriosclerosis with mild dissecting interstitial fibrosis and variable myofiber hypertrophy. Hematoxylin and eosin. Figures 13 and 14. Heart from a geriatric female chimpanzee with a history of sudden cardiac death. Figure 13. Anterior view of heart demonstrates cardiomegaly and interstitial fibrosis. Figure 14. Transverse section of the heart at 3 cm from apex demonstrates left ventricular hypertrophy. (University of Illinois Zoological Pathology Program archives).

Left ventricular hypertrophy, as well as arteriosclerosis of intrinsic coronary arteries, suggests the possibility of hypertension as an underlying pathogenesis for fibrosing cardiomyopathy in apes. ^221,248,276

Hypertension

Hypertension in humans increases with age, and it is estimated that >60% of individuals >65 yo are hypertensive. Increasing arterial stiffness is thought to be important in the pathogenesis. ^247,248 Metabolic syndrome, which increases with age (see above), also contributes to vascular stiffness and hypertension. Other factors include chronic inflammation (“inflammaging”), abnormal sympathetic nervous system activity, psychosocial/life stress, and chronic renal disease. ^32,43,64 Salt sensitivity increases with age (likely due to changes in the renal interstitium and associated changes in renin/angiotensin), contributing to hypertension. ¹⁵²

As mentioned above, heart lesions in the apes are suggestive of hypertension, and several lines of evidence support this hypothesis. First is the echocardiographic pattern and gross morphology of the ape hearts with generally concentric left ventricular hypertrophy. The histologic changes are also compatible: polyploid hypertrophied myocytes and dissecting interstitial fibrosis, rather than large foci suggestive of true infarction. ^222,230,248 There are also changes in intramural (intrinsic) coronary arteries suggestive of hypertension, at least in gorillas and orangutans. ⁶⁴ Changes in small-caliber vessels are those of mural thickening and luminal narrowing, brought about by either “eutrophic inward remodeling” or smooth muscle cell hypertrophy. ¹¹³ Altered character and amount of extracellular matrix and mural hyalinization suggestive of leakage of plasma into the wall due to endothelial dysfunction also contribute to the appearance of hyaline arteriosclerosis. ^{36, 84, 162} The arterial change is often segmental within the intramural (intrinsic) coronary arteries and arterioles. In contrast, the larger epicardial coronary vessels are usually unaffected, similar to “small vessel disease” in humans. ¹⁷⁷

Definitive proof of the relationship between hypertension and ape heart disease relies on antemortem demonstration of hypertension. Developing antemortem normal blood pressure reference ranges and documenting hypertension has been difficult in the apes because compliance with awake blood pressure monitoring requires extensive training and validation of methodology (documenting peripheral vs central pressures). Most reports of blood pressure monitoring are in sedated or anesthetized animals, and anesthetic protocols can affect these values. Blood pressure reference ranges have been reported for chimpanzees. ⁶⁸ Diastolic pressure was documented to increase with obesity in females but not in males. However, males in general had higher diastolic pressures than females. Age was a factor in elevated diastolic blood pressure but not systolic. ⁶⁹ Experimental dietary studies in chimpanzees have shown individual variability with regard to “salt sensitivity” and development of hypertension, but the presence of concurrent renal disease or other confounding factors was not investigated. ⁶³

Hypertension was diagnosed antemortem in 2 bonobos, a mother and son, who both died of stroke (Dr Victoria Clyde, Bonobo SSP, personal communication). The male had massive cardiomegaly and an aortic dissection. Both had histologic vascular changes of hypertension, and both had myocardial fibrosis, although only the male’s heart was enlarged. Hypertension was diagnosed antemortem in 2 gorillas (based on blood pressure measurements during anesthetic events). In a 34 yo female, there was marked left ventricular hypertrophy (free wall 2.6 cm thick) and median hypertrophy with “onion skin fibrosis” in small arteries in the retina, choroid, and meninges of the brain, kidney, and heart. ¹⁸⁵ In a 28 yo male, hypertension was documented over a 2 y period. ¹⁷¹ He developed congestive heart failure and died under anesthesia. The heart was dilated with marked interstitial fibrosis and more mild fatty infiltration in the left ventricle, as well as mural thickening of small arterioles. Hypertension was suspected to be the etiology of left ventricular hypertrophy, cardiogenic death, and historical stroke in a 32 yo orangutan. ²⁷⁶ Renal changes compatible with hypertension were also documented.

Aortic Dissections: Further Evidence for Hypertension?

In humans, the mean age of aortic dissections is 63 y, and males account for 65% of cases. ¹⁸⁶ The most common risk factors are hypertension and connective tissue disorders such as Marfan syndrome. Aortic dissections have been identified as a major problem causing sudden death in gorillas. ¹³² Of 8 affected gorillas in that report, 6 were males. Ages ranged from 16 to 43 yo (mean age 31 y). All dissections were in the ascending aorta (DeBakey type II, Stanford type A) with rupture of the aorta occurring just distal to the aortic valves or within an aortic sinus (Fig. 15). It is the second-most common cardiovascular problem in gorillas. Similar dissections have caused death in 4 male bonobos (13.7–25.7 yo; SSP database) and 1 chimpanzee >35 yo. ⁸⁵ These data help support the contention that hypertension is a plausible explanation for “fibrosing cardiomyopathy.” However, no dissections have been identified, to our knowledge, in orangutans, which also suffer from “fibrosing cardiomyopathy.” Since myocardial fibrosis is an “end point” with many possible pathogeneses, it would actually be surprising if hypertension were the entire “answer” to all ape heart disease. ^58,141

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Figure 15. Stanford type A aortic dissection, ascending aorta, 34-year-old male lowland gorilla. This animal died unexpectedly due to cardiac tamponade. (Courtesy of San Diego Zoo Global). Figure 16. Atherosclerosis, intrinsic (intramural) coronary arteriole, papillary muscle, left ventricle, 39-year-old female lowland gorilla that was euthanized because of a massive hemorrhagic stroke. This single arteriole was segmentally affected. Hematoxylin and eosin. Figure 17. Severe atherosclerosis, distal aorta, and iliac bifurcation; 42-year-old male orangutan. The aortic and iliac arterial intima is disrupted by multifocal to coalescing yellow atherosclerotic plaques with multifocal ulceration and mineralization. (Courtesy of San Diego Zoo Global). Figure 18. Severe nodular myxomatous degeneration with fibrosis, intravalvular hemorrhage, and hemosiderosis; mitral valve, 48-year-old female zoo-housed chimpanzee. There was severe concentric left ventricular hypertrophy and mild dissecting interstitial fibrosis. (University of California Davis William R. Pritchard Veterinary Medical Teaching Hospital archives). Figure 19. Fibrosis and mineralization, aortic valve, 47-year-old lowland gorilla with a history of sudden death. This lesion resembles aortic valve sclerosis of elderly humans. (University of California Davis William R. Pritchard Veterinary Medical Teaching Hospital archives). Figure 20. Hyperplastic arteriosclerosis, small renal capsular artery, 35-year-old male gorilla with aortic dissection. The arteriolar changes in the kidney were suggestive of hypertension. Periodic acid Schiff–hematoxylin–Mason’s trichrome. (Courtesy of Dr C. A. Brown).

Atherosclerosis

Although the pathology data do not support coronary atherosclerosis as a cause of chimpanzee heart disease, it still warrants examination as a possible aging change in apes. ²⁶⁰ In humans, atherosclerosis increases with age, and atherosclerosis of coronary arteries is the most common cause of cardiac deaths and congestive heart failure among elderly humans. ^273,274 The pathogenesis of atherosclerosis is still not completely elucidated. Current understanding is that it is the result of complex processes involving endothelial damage, inflammation, dyslipidemias, and changes in arterial intercellular matrix. ^230,273,274 Cardiovascular risk factors such as hypertension and dyslipidemias contribute to the initial endothelial damage as well as to subsequent events in the progression of the disease.

Does atherosclerosis occur in captive or wild apes? Literature from the 1960s and 1970s stated that chimpanzees had the highest “rate” of spontaneous atherosclerosis of any nonhuman primate species, and chimpanzees have been used as animal models for atherosclerosis induced by “atherogenic” diets. ¹⁶⁵ More recent studies of laboratory-housed chimpanzees found that only 3 of 29 chimpanzees with myocardial fibrosis had mild atherosclerosis. ¹⁴² Another study identified 8 of 87 chimps with arteriosclerosis/atherosclerosis with a mean age of 33 yo, which was significantly older than those without arterial disease. ²²⁵ Affected vessels were in brain (n = 4), aorta (n = 3), kidney (n = 1), heart (n = 1), and adrenal (n = 1), confirming that atherosclerosis was not typically associated with heart disease in chimpanzees. In zoo chimpanzees examined by one of us (L.J.L.), aortic atherosclerosis was seen in a 34 yo female and a 56 yo male, both without coronary atherosclerosis. Clinical studies in chimpanzees have suggested that hypercholesterolemia and dyslipidemias are not predictive of atherosclerosis. ²⁶⁰

In gorillas, plaques/grade I atheromas were demonstrated by transesophageal echocardiography in the ascending and descending aorta in gorillas 10, 26, 27, and 36 yo and grade II atheroma in a 40 yo male, suggesting that severity increases with age. ²² Plaques were correlated with decreased high-density lipoprotein, increased cholesterol:high-density lipoprotein ratio and increased ApoB/ApoA1 but not total cholesterol alone. In our experience, coronary artery atherosclerosis is rare in gorillas, although in the past CAD was reported to have caused myocardial infarction in gorillas. ¹⁰¹ We have seen atherosclerosis involving small-caliber intrinsic coronary arterioles in the absence of involvement of the larger epicardial vessels in only 2 gorillas: a 34 yo male with chronic heart failure and a 39 yo female with hypertension and stroke (Fig. 16).

Atherosclerosis in zoo orangutans is less well described. A 20 yo female died with myocardial infarction associated with left anterior descending coronary artery atherosclerosis. ²²³ She had a history of high total cholesterol values (329 and 341 mg/dl). In adult orangutans examined by one of us (L.J.L.), including 5 males (12, 28, 33, 34, and 39 yo) and 4 females (12, 15, 45 and 56 yo), atherosclerosis has been confined to the aorta, with the most severe lesions in the caudal abdominal aorta and internal iliac arteries in the older males (Fig. 17).

Based on the above, under current management practices, we agree with the contention that coronary arterial atherosclerosis is rare, not only in chimpanzees, but in all the apes. ²⁶⁰ The significance and pathophysiology of atherosclerosis in the aorta of great apes, particularly orangutans, bear further investigation.

Cardiac Valvular Disease

The 2 main forms of valvular disease in aging humans are myxomatous degeneration of the mitral valve (well known to veterinary pathologists because of the similar condition in dogs) and sclerosis and calcification of the aortic valve. ^19,231 Aging changes in the human mitral valve include increase in polyglycans, increase and remodeling of collagen, and decrease in elastin. Myxomatous degeneration in humans is not considered to be part of normal aging, but when it occurs, it becomes clinically significant in the sixth decade of life and is associated with either mitral insufficiency or mitral stenosis. Aortic valve sclerosis and calcification is a disease of elderly humans and is characterized by stiffening of aortic valve margins and nodular deposition of fibrous tissue with calcification and, occasionally, bone formation. ²⁵⁷

Other than infective valvular endocarditis, valvular disease has not been well described in the apes. Isolated valvular lesions were very rare in echocardiograms of 99 western lowland gorillas, although mild mitral regurgitation was been noted. ¹⁸⁰ In the apes that we examined, infective valvular disease was seen in a few mountain gorillas, and myxomatous degeneration of mitral valve was diagnosed in three >30 yo mountain gorilla females, a 42 yo male orangutan, and a 48 yo female zoo chimpanzee (Fig. 18). A single case of aortic valve fibrosis and mineralization was diagnosed clinically and confirmed on cardiac necropsy in a 47 yo male zoo gorilla (Fig. 19).

The high prevalence of heart disease in captive apes is cause for great concern in the zoo and laboratory communities. Much work is needed to better define the lesions and pathogenesis. To this end, the Great Ape Heart Project (GAHP), based at Zoo Atlanta, has developed standardized protocols for ante- and postmortem evaluation of ape hearts and a relational database that will allow analysis of clinical and necropsy data to better understand, diagnose, treat, and ideally prevent great ape heart disease (see http://greatapeheartproject.org/).

Cardiovascular Disease in Wild Apes

An important and not yet completely answered question is whether cardiovascular disease, particularly “fibrosing cardiomyopathy,” is found in wild apes or if it is the result of captive management. In a limited study of wild chimpanzees, myofiber hypertrophy as evidenced by karyomegaly (polyploidy) was seen even in immature animals, but fibrosis was present in only 2 individuals: an aged female (44 yo) and an adult male (28 yo). ²⁵³ Arteriosclerosis was not noted in those animals. In a review of causes of mortality in mountain gorillas, cardiovascular disease was considered to be the cause of death in only 3% of animals. ¹⁸⁹ Both male and females were involved. More recently a higher prevalence was noted in eastern lowland gorillas (G. b. graueri) from an isolated population on Mt Tshiaberimu in the Democratic Republic of Congo. ¹³¹ Lesions included myocardial fibrosis and arteriosclerosis in intrinsic coronary arteries, along with marked myofiber hypertrophy as described in zoo-housed lowland gorillas. Atherosclerosis has not been identified in coronary arteries of wild mountain gorillas, but fatty streaks and plaques have been seen in the aortas of 2 geriatric females, 35 and 39 yo, both of whom were cachectic and had advanced cancers. Additional necropsies with detailed examination of the heart, based on protocols developed by the GAHP, are needed to determine the nature and extent of cardiovascular disease in wild apes.

Renal Aging

Renal senescence is a common but not universal occurrence in elderly humans. This term encompasses decline in renal function as well as decreased ability to respond to acute injuries. Renal aging is viewed as a complex process with multiple etiologies; the pathophysiology has been the subject of several excellent reviews of the aging human kidney and rodent models. ^{31,159,161,275} In humans, it is influenced by sex (males > females), race (African Americans > Caucasians), genetics, and the presence of cardiovascular disease. Genomic studies have shown kidney aging to be associated with differential expression in as many as 500 genes, including increased expression of immune and inflammatory proteins, increased synthesis and turnover of interstitial matrix, increase in oxidative stress markers, and decreased expression of genes associated with collagen degradation and metabolic processes. ³¹ For example, expression of the klotho gene appears to be particularly important in suppressing age-related changes in kidney and other organs. ³¹ In addition, upregulation of acute- and chronic-phase reactants provides important markers of microinflammation, which contributes to injury and aging in kidney and heart. ²⁵¹

Aging is accompanied by functional as well as morphologic changes. Several studies stress that creatinine clearance and glomerular filtration rate (GFR) decrease up to 55% in individuals >80 yo, when compared with maximum GFR of people in their 20s or 30s (<60 vs 90–120 ml/min/1.73 m²). ¹⁵⁹ Interestingly, decline in GFR is not always accompanied by increases above the reference intervals for blood urea nitrogen (BUN) and creatinine, possibly due to altered dynamics of creatinine production due to sarcopenia and diet in the elderly. It was suggested by some authors that the reference range for normal creatinine should be lowered for the elderly. It was also suggested that low GFR not be used to diagnose renal dysfunction in the absence of proteinuria or other evidence of renal disease. ³¹

Another important functional change is decreased renal blood flow, including actual flow and that in relation to total cardiac output. ¹⁶¹ Morphologic correlates in kidneys of elderly humans and rodent models include vascular changes such as arteriosclerosis and arteriolosclerosis, median smooth muscle hypertrophy, and intimal fibrosis, which are similar to changes seen in younger adults afflicted with hypertension and diabetes. ^{31, 161} Eventually, altered blood flow leads to glomerular sclerosis and obsolescence in the outer cortex, with associated tubular atrophy and interstitial fibrosis in both cortex and medulla. In addition to collagen accumulation, accumulation of normal matrix constituents (eg, hyaluronan) and abnormal constituents (eg, advanced glycation end products) contributes to increased extracellular matrix in the glomerular mesangium and in the tubulointerstitium. ^31,152,161 In the medulla, abnormal interstitium can significantly alter fluid and sodium balance and may account for the “salt sensitivity” of the elderly. ¹⁵² Other histologic changes in elderly kidneys may include epithelial tubular lipofuscinosis and nonspecific infiltration of the interstitium by inflammatory cells, primarily lymphocytes and macrophages, in both cortex and medulla. This change is consistent with chronic interstitial nephritis and is similar to changes seen in older dogs and cats. The diagnosis of “chronic interstitial nephritis” in humans is usually confined to specific inflammatory conditions, while in veterinary medicine it has a much broader connotation. Nonetheless, interstitial inflammation is considered an important contribution to chronic renal disease in humans. ²⁰⁵

Clinically, declining renal function appears to be common in aging laboratory-housed chimpanzees. ²⁶⁴ This is evidenced by increasing levels of BUN and creatinine in male chimpanzees beginning in the 25 to 30 yo range and in females in the 30- to 35 yo range. Increased urine protein:creatinine ratios in chimps >24.5 yo revealed protein leakage suggestive of abnormal glomerular function. ¹⁴³ In a clinical study of 16 female chimps >35 yo, renal disease was present in 31.5% and characterized as nephrotic syndrome in 3 animals, hydronephrosis in one and “unclassified renal disease” in another. ¹⁸⁸

In contrast to the above laboratory chimpanzee studies, it must be noted that renal diagnoses in zoo-housed apes derive from compiled necropsy reports, which are typically based on light microscopy alone and not always supported by clinical renal data. However, the accurate diagnosis of glomerular disease depends on the use of light microscopy, electron microscopic, and immunofluorescent techniques. All 3 modalities are routinely used in human nephropathology and have recently been used, along with clinical data, in dogs to diagnose glomerular disease. ⁵³ To date, such detailed analyses have not been performed in zoo animals, but complementary retrospective and prospective renal studies are planned activities of the GAHP, as part of ape cardiovascular disease investigation (see above).

In mortality reviews of zoo chimpanzees, chronic renal disease was considered the cause of death in 3 of 24 (12.5%) adults 10 to 35 yo but in none of the 11 animals >35 yo. ⁸⁵ Severe renal lesions consisting of membranous glomerulopathy with multifocal global sclerosis and tubular protein were seen in 2 older adult wild chimpanzees (K.A.T.), but overall prevalence of renal disease in wild chimpanzees is yet to be determined. Renal lesions in laboratory chimpanzees and the connection between cardiac and renal disease are covered in another paper in this issue of Veterinary Pathology. ⁵²

In other apes, renal vascular lesions and interstitial fibrosis were seen in the 2 hypertensive bonobos, highlighted above in the Hypertension section. Renal disease was considered to be the cause of death in 26% of the 15 orangutans >40 yo but in only 16% to 18% of the 95 younger adults 20 to 40 yo. ¹⁵⁵ Renal disease was a comorbidity in an additional 20 younger adults (21%) and 5 older adults (33%). The most common diagnoses were “chronic interstitial nephritis,” “chronic glomerulonephritis,” and “end-stage kidney.” The etiology is uncertain and likely not the same in all cases. In some older males, interstitial nephritis was suspected to be associated with previous bouts of cystitis and ascending infection. Hypertension may be playing a role in renal disease in some orangutans; in at least 1 older male that we examined, there were glomerular and renal vascular lesions suggestive of underlying hypertension. Additional support for this possibility comes from the orangutan SSP mortality review. ¹⁵⁵ For 122 of 168 orangutans >15 yo (subadult males, adults/old adults of both sexes), cardiovascular disease, respiratory infections, and renal disease were the most frequent primary, secondary, or tertiary causes of death. In animals with >1 of these diagnoses, a statistical association was noted between cardiovascular and renal disease but not cardiovascular and respiratory disease or renal and respiratory disease (SSP, unpublished data).

An interesting morphologic change observed in 3 adult male orangutans was dense accumulation of tubular epithelial pigment (lipofuscin)—periodic acid–Schiff positive, Perl’s negative—that was grossly visible as greenish-brown discoloration of the outer stripe of the medulla. This change was not seen in the kidneys of any other apes that we examined.

In contrast to orangutans, renal disease was considered the cause of death in only 1 adult female lowland gorilla and 1 wild mountain gorilla, both of which had pyelonephritis. ^170,189 However, renal disease as a comorbidity was not investigated in either of these gorilla studies. Incidental aging changes that we observed in captive and wild gorilla kidneys include medullary interstitial hyalinization, due to an increase in extracellular matrix positive for Masson’s trichrome and periodic acid–Schiff, and mild multifocal cortical interstitial and periglomerular fibrosis. In 1 male gorilla dying of aortic dissection, hypertrophic changes in small renal arterioles were suggestive of hypertension (Fig. 20). More detailed investigation of gorilla renal disease is needed.