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1.  MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation 
Nature cell biology  2015;17(8):1049-1061.
The TOR (target of rapamycin) kinase limits longevity by poorly understood mechanisms. Rapamycin suppresses the mammalian TORC1 complex, which regulates translation, and extends lifespan in diverse species, including mice. We show that rapamycin selectively blunts the pro-inflammatory phenotype of senescent cells. Cellular senescence suppresses cancer by preventing cell proliferation. However, as senescent cells accumulate with age, the senescence-associated secretory phenotype (SASP) can disrupt tissues and contribute to age-related pathologies, including cancer. MTOR inhibition suppressed the secretion of inflammatory cytokines by senescent cells. Rapamycin reduced IL6 and other cytokine mRNA levels, but selectively suppressed translation of the membrane-bound cytokine IL1A. Reduced IL1A diminished NF-κB transcriptional activity, which controls much of the SASP; exogenous IL1A restored IL6 secretion to rapamycin-treated cells. Importantly, rapamycin suppressed the ability of senescent fibroblasts to stimulate prostate tumour growth in mice. Thus, rapamycin might ameliorate age-related pathologies, including late-life cancer, by suppressing senescence-associated inflammation.
doi:10.1038/ncb3195
PMCID: PMC4691706  PMID: 26147250
2.  Reduced Expression of MYC Increases Longevity and Enhances Healthspan 
Cell  2015;160(3):477-488.
SUMMARY
MYC is a highly pleiotropic transcription factor whose deregulation promotes cancer. In contrast, we find that Myc haploinsufficient (Myc+/−) mice exhibit increased lifespan. They show resistance to several age-associated pathologies, including osteoporosis, cardiac fibrosis and immunosenescence. They also appear to be more active, with a higher metabolic rate and healthier lipid metabolism. Transcriptomic analysis reveals a gene expression signature enriched for metabolic and immune processes. The ancestral role of MYC as a regulator of ribosome biogenesis is reflected in reduced protein translation, which is inversely correlated with longevity. We also observe changes in nutrient and energy sensing pathways, including reduced serum IGF-1, increased AMPK activity, and decreased AKT, TOR and S6K activities. In contrast to observations in other longevity models, Myc+/− mice do not show improvements in stress management pathways. Our findings indicate that MYC activity has a significant impact on longevity and multiple aspects of mammalian healthspan.
doi:10.1016/j.cell.2014.12.016
PMCID: PMC4624921  PMID: 25619689
3.  Phenotypic Features of Circulating Leukocytes from Non-human Primates Naturally Infected with Trypanosoma cruzi Resemble the Major Immunological Findings Observed in Human Chagas Disease 
PLoS Neglected Tropical Diseases  2016;10(1):e0004302.
Background
Cynomolgus macaques (Macaca fascicularis) represent a feasible model for research on Chagas disease since natural T. cruzi infection in these primates leads to clinical outcomes similar to those observed in humans. However, it is still unknown whether these clinical similarities are accompanied by equivalent immunological characteristics in the two species. We have performed a detailed immunophenotypic analysis of circulating leukocytes together with systems biology approaches from 15 cynomolgus macaques naturally infected with T. cruzi (CH) presenting the chronic phase of Chagas disease to identify biomarkers that might be useful for clinical investigations.
Methods and Findings
Our data established that CH displayed increased expression of CD32+ and CD56+ in monocytes and enhanced frequency of NK Granzyme A+ cells as compared to non-infected controls (NI). Moreover, higher expression of CD54 and HLA-DR by T-cells, especially within the CD8+ subset, was the hallmark of CH. A high level of expression of Granzyme A and Perforin underscored the enhanced cytotoxicity-linked pattern of CD8+ T-lymphocytes from CH. Increased frequency of B-cells with up-regulated expression of Fc-γRII was also observed in CH. Complex and imbricate biomarker networks demonstrated that CH showed a shift towards cross-talk among cells of the adaptive immune system. Systems biology analysis further established monocytes and NK-cell phenotypes and the T-cell activation status, along with the Granzyme A expression by CD8+ T-cells, as the most reliable biomarkers of potential use for clinical applications.
Conclusions
Altogether, these findings demonstrated that the similarities in phenotypic features of circulating leukocytes observed in cynomolgus macaques and humans infected with T. cruzi further supports the use of these monkeys in preclinical toxicology and pharmacology studies applied to development and testing of new drugs for Chagas disease.
Author Summary
T. cruzi is the parasite responsible for Chagas disease, a neglected tropical illness, present in endemic and also in non-endemic countries. T. cruzi parasites are spread mainly by a vector’s bite but can also be transmitted by blood transfusion, organ transplant, laboratory accidents, congenitally and by ingestion of contaminated food. Non-human primates that are also predisposed to become infected, live in places where vectors and T. cruzi exist. Similar clinical sequelae are observed in these animals when compared to humans who are infected with T. cruzi. A better understanding of the pathogenesis of T. cruzi-infected non-human primates may bring new advances to understanding human infection. Here, we explored the immunological features of cynomolgus macaques naturally infected by T. cruzi, aiming to contribute to the validation of this species as an appropriate experimental model. Infected animals displayed a similar immunological profile to that observed in humans, with high activity of cytotoxic cells and expansion of macrophages and T-cell subsets. Furthermore, by using bioinformatics tools, we demonstrated that CD14+CD56+ and CD3+HLA-DR+ cells are major determinants to segregate CH from NI group, followed by innate and adaptive cell subpopulations. Altogether, our data suggest that non-human primates are an appropriate model to study Chagas disease.
doi:10.1371/journal.pntd.0004302
PMCID: PMC4726540  PMID: 26808481
4.  The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs 
Aging Cell  2015;14(4):644-658.
The healthspan of mice is enhanced by killing senescent cells using a transgenic suicide gene. Achieving the same using small molecules would have a tremendous impact on quality of life and the burden of age-related chronic diseases. Here, we describe the rationale for identification and validation of a new class of drugs termed senolytics, which selectively kill senescent cells. By transcript analysis, we discovered increased expression of pro-survival networks in senescent cells, consistent with their established resistance to apoptosis. Using siRNA to silence expression of key nodes of this network, including ephrins (EFNB1 or 3), PI3Kδ, p21, BCL-xL, or plasminogen-activated inhibitor-2, killed senescent cells, but not proliferating or quiescent, differentiated cells. Drugs targeting these same factors selectively killed senescent cells. Dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse BM-MSCs. The combination of dasatinib and quercetin was effective in eliminating senescent MEFs. In vivo, this combination reduced senescent cell burden in chronologically aged, radiation-exposed, and progeroid Ercc1−/Δ mice. In old mice, cardiac function and carotid vascular reactivity were improved 5 days after a single dose. Following irradiation of one limb in mice, a single dose led to improved exercise capacity for at least 7 months following drug treatment. Periodic drug administration extended healthspan in Ercc1−/Δ mice, delaying age-related symptoms and pathology, osteoporosis, and loss of intervertebral disk proteoglycans. These results demonstrate the feasibility of selectively ablating senescent cells and the efficacy of senolytics for alleviating symptoms of frailty and extending healthspan.
doi:10.1111/acel.12344
PMCID: PMC4531078  PMID: 25754370
dasatinib; dependence receptors; ephrins; p21; PI3K delta; plasminogen-activated inhibitor; quercetin
5.  Removal of growth hormone receptor (GHR) in muscle of male mice replicates some of the health benefits seen in global GHR−/− mice 
Aging (Albany NY)  2015;7(7):500-512.
Global disruption of the GH receptor in mice (GHR−/−) produces a large and reproducible extension in lifespan. Since lack of GH action in muscle resulting in improved glucose homeostasis is potentially a mechanism by which GHR−/− mice are long-lived, and since no information on muscle-specific GHR disruption in females is available, we generated and characterized a line of muscle-specific GHR disrupted (MuGHRKO) mice. As expected, male MuGHRKO mice had improved fasting blood glucose, insulin, c-peptide, and glucose tolerance. In contrast, female MuGHRKO mice exhibited normal glucose, insulin, and glucose tolerance. Body weight was mildly but significantly altered in opposite directions in males (decreased) and females (increased) compared to controls. Grip strength and treadmill endurance were unchanged with advanced age in both sexes, suggesting that the direct action of GH on muscle has minimal effect on age-related musculoskeletal frailty. Longevity was unchanged in both sexes at Ohio University and significantly increased for males at University of Michigan. These data suggest that removal of GHR in muscle of male MuGHRKO mice replicates some of the health benefits seen in global GHR−/− mice including improvements to glucose homeostasis and smaller body weight in males, which may explain the trends observed in lifespan.
PMCID: PMC4543039  PMID: 26233957
growth hormone receptor (GHR); muscle-specific knockout; lifespan; aging; frailty; pathology; body composition
6.  Mortality in Captive Baboons (Papio spp.): A 23 Year Study 
Journal of medical primatology  2014;43(3):169-196.
Background
We report the causes of mortality for 4,350 captive baboons that died or were euthanized due to natural causes during a 23 year period at the Southwest National Primate Research Center.
Methods
Necropsy records were retrieved and reviewed to determine a primary cause of death or indication for euthanasia. Data was evaluated for morphological diagnosis, organ system and etiology.
Results
The 20 most common morphologic diagnoses accounted for 76% of the cases, including: stillborn (10.8%); colitis (8.6%); hemorrhage (8.4%); ulcer (5.2%); seizures (4.7%); pneumonia (4.2%); inanition (4.1%); dermatitis (3.8%); spondylosis (3.3%); and amyloidosis (3.0%). The digestive system was most frequently involved (21.3%), followed by the urogenital (20.3%), cardiovascular (12.2%), and multisystem disease (10.3%). An etiology was not identified in approximately one third of cases. The most common etiologies were trauma (14.8%), degenerative (9.5%), viral (8.7%), and neoplastic/proliferative (7.0%).
Conclusion
This information should be useful for individuals working with baboons.
doi:10.1111/jmp.12101
PMCID: PMC3989440  PMID: 24483852
Nonhuman primate; Disease; Epidemiology; Cancer; Pathology; Spontaneous; Survey; Age at death; Lifespan; Morbidity
7.  ENDOCANNABINOID CROSSTALK BETWEEN PLACENTA AND MATERNAL FAT IN A BABOON MODEL (Papio spp.) OF OBESITY 
Placenta  2013;34(11):10.1016/j.placenta.2013.08.007.
Introduction
Maternal obesity (MO) remains a serious obstetric problem with acute and chronic morbidities for both mothers and offspring. The mechanisms underlying these adverse consequences of MOremain unknown. Endocannabinoids (ECB) are neuromodulatory lipids derived from adipocytes. Metabolic crosstalk between placenta and adipocytes may mediate sequelae of MO. The goal of this study was to elucidate placental and systemic ECBs in MO.
Material and methods
Placentas, serum, and subcutaneous fat were collected at Cesarean sections performed near term (0.9 G) in four non-obese (nOB) and four obese (OB) baboons (Papio spp.). Concentrations of anandamide (AEA) and 2-arachidonoylglycerol (2-AG) were measured by liquid chromatography coupled to tandem mass spectrometry. AEA and 2-AG pathways were characterized in placentas by Q-RT-PCR, Western blot, and immunohistochemistry.
Results
Placental 2-AG levels were lower and maternal fat AEA levels were higher in OB (1254.1 ± 401.3 nmol/kg and 17.3 ± 4 nmol/kg ) vs. nOB (3124.2 ± 557.3 nmol/kg and 3.1 ± 0.6 nmol/kg) animals. Concentrations of 2-AG correlated positively between maternal fat and placenta (r=0.82, p=0.013), but correlated negatively with maternal leptin concentrations (r=−0.72, p=0.04 and r=−0.83, p=0.01, respectively).
Conclusion
This is the first study to demonstrate differential ECB pathway regulation in maternal fat and placenta in MO. Differential regulation and function exist for AEA and 2-AG as the major ECB pathways in placenta.
doi:10.1016/j.placenta.2013.08.007
PMCID: PMC3827983  PMID: 24008071
8.  Reductions in serum IGF-1 during aging impair health span 
Aging Cell  2013;13(3):408-418.
In lower or simple species, such as worms and flies, disruption of the insulin-like growth factor (IGF)-1 and the insulin signaling pathways has been shown to increase lifespan. In rodents, however, growth hormone (GH) regulates IGF-1 levels in serum and tissues and can modulate lifespan via/or independent of IGF-1. Rodent models, where the GH/IGF-1 axis was ablated congenitally, show increased lifespan. However, in contrast to rodents where serum IGF-1 levels are high throughout life, in humans, serum IGF-1 peaks during puberty and declines thereafter during aging. Thus, animal models with congenital disruption of the GH/IGF-1 axis are unable to clearly distinguish between developmental and age-related effects of GH/IGF-1 on health. To overcome this caveat, we developed an inducible liver IGF-1-deficient (iLID) mouse that allows temporal control of serum IGF-1. Deletion of liver Igf -1 gene at one year of age reduced serum IGF-1 by 70% and dramatically impaired health span of the iLID mice. Reductions in serum IGF-1 were coupled with increased GH levels and increased basal STAT5B phosphorylation in livers of iLID mice. These changes were associated with increased liver weight, increased liver inflammation, increased oxidative stress in liver and muscle, and increased incidence of hepatic tumors. Lastly, despite elevations in serum GH, low levels of serum IGF-1 from 1 year of age compromised skeletal integrity and accelerated bone loss. We conclude that an intact GH/IGF-1 axis is essential to maintain health span and that elevated GH, even late in life, associates with increased pathology.
doi:10.1111/acel.12188
PMCID: PMC4326899  PMID: 24341939
aging; bone; growth hormone; IGF; insulin-sensitivity; LID; lifespan; liver; tumor
9.  Pathology of spontaneous air sacculitis in 37 baboons and 7 chimpanzees and a brief review of the literature 
Journal of Medical Primatology  2012;41(4):266-277.
Background
Air sacculitis is an important clinical condition in non-human primates.
Methods
We evaluated 37 baboons and 7 chimpanzees with spontaneous air sacculitis submitted to pathology over a 20 year period.
Results
Air sacculitis was observed almost exclusively in males. Common reported signs were halitosis, coughing, nasal discharges, depression, anorexia, and weight loss. Gross lesions included thickened air sacs and suppurative exudate lining the walls. Microscopic lesions included marked epithelial hyperplasia or hypertrophy, necrosis, fibrosis, cellular infiltrates, and bacterial colonies. Mixed bacterial infections were more common than infections by single species of bacteria. Streptococcus sp. was the most frequent bacteria isolated in both baboons and chimpanzees.
Conclusions
This is the first report describing the gross and microscopic lesions of air sacculitis in chimpanzees. The preponderance of males suggests a male sex predilection in baboons.
doi:10.1111/j.1600-0684.2012.00547.x
PMCID: PMC3402580  PMID: 22765381
Air sac; Airsacculitis; Pan; Papio; Non-human primate
10.  Craniorachischisis and Omphalocele in a Stillborn Cynomolgus Monkey (Macaca fascicularis) 
Nonhuman primates have been a common animal model to evaluate experimentally-induced malformations. Reports on spontaneous malformations are important in determining the background incidence of congenital anomalies in specific species and in evaluating experimental results. Here we report on a stillborn cynomolgus monkey (Macaca fascicularis) with multiple congenital anomalies from the colony maintained at the Southwest National Primate Research Center at the Southwest Foundation for Biomedical Research, San Antonio, Texas. Physical findings included low birth weight, craniorachischisis, facial abnormalities, omphalocele, malrotation of the gut with areas of atresia and intussusception, a Meckel diverticulum, arthrogryposis, patent ductus arteriosus, and patent foramen ovale. The macaque had normal male external genitalia, but undescended testes. Gestational age was unknown but was estimated from measurements of the limbs and other developmental criteria. Although cytogenetic analysis was not possible due to the tissues being in an advanced state of decomposition, array Comparative Genomic Hybridization analysis using human bacterial artificial chromosome clones was successful in effectively eliminating aneuploidy or any copy number changes greater than approximately 3–5 Mb as a cause of the malformations. Further evaluation of the animal included extensive imaging of the skeletal and neural tissue defects. The animal’s congenital anomalies are discussed in relation to the current hypotheses attempting to explain the frequent association of neural tube defects with other abnormalities.
doi:10.1002/ajmg.a.33627
PMCID: PMC3678351  PMID: 21567905
neural tube defects; schisis association; macaque; cynomolgus monkey; non-human primate; congenital defects; malformations
11.  Thioredoxin, oxidative stress, cancer and aging 
The Free Radical or Oxidative Stress Theory of Aging is one of the most popular theories in aging research and has been extensively studied over the past several decades. However, recent evidence using transgenic/knockout mice that overexpress or down-regulate antioxidant enzymes challenge the veracity of this theory since the animals show no increase or decrease in lifespan. These results seriously call into question the role of oxidative damage/stress in the aging process in mammals. Therefore, the theory requires significant modifications if we are to understand the relationship between aging and the regulation of oxidative stress. Our laboratory has been examining the impacts of thioredoxins (Trxs), in the cytosol and mitochondria, on aging and age-related diseases. Our data from mice that are either up-regulating or down-regulating Trx in different cellular compartments, that is, the cytosol or mitochondria, could shed some light on the role of oxidative stress and its pathophysiological effects. The results generated from our lab and others may indicate that: 1) changes in oxidative stress and the redox state in the cytosol, mitochondria or nucleus might play different roles in the aging process; 2) the role of oxidative stress and redox state could have different pathophysiological consequences in different tissues/cells, for example, mitotic vs. post-mitotic; 3) oxidative stress could have different pathophysiological impacts in young and old animals; and 4) the pathophysiological roles of oxidative stress and redox state could be controlled through changes in redox-sensitive signaling, which could have more diverse effects on pathophysiology than the accumulation of oxidative damage to various molecules. To critically test the role of oxidative stress on aging and age-related diseases, further study is required using animal models that regulate oxidative stress levels differently in each cellular compartment, each tissue/organ, and/or at different stages of life (young, middle and old) to change redox sensitive signaling pathways.
doi:10.1186/2046-2395-1-4
PMCID: PMC3886257  PMID: 24764510
Thioredoxin; Transgenic mouse; Knockout mouse; Oxidative stress; Cancer; aging
12.  Do Ames dwarf and calorie-restricted mice share common effects on age-related pathology? 
Pathobiology of Aging & Age Related Diseases  2013;3:10.3402/pba.v3i0.20833.
Since 1996, aging studies using several strains of long-lived mutant mice have been conducted. Among these studies, Ames dwarf mice have been extensively examined to seek clues regarding the role of the growth hormone/insulin-like growth factor-1 axis in the aging process. Interestingly, these projects demonstrate that Ames dwarf mice have physiological characteristics that are similar to those seen with calorie restriction, which has been the most effective experimental manipulation capable of extending lifespan in various species. However, this introduces the question of whether Ames dwarf and calorie-restricted (CR) mice have an extended lifespan through common or independent pathways. To answer this question, we compared the disease profiles of Ames dwarf mice to their normal siblings fed either ad libitum (AL) or a CR diet. Our findings show that the changes in age-related diseases between AL-fed Ames dwarf mice and CR wild-type siblings were similar but not identical. Moreover, the effects of CR on age-related pathology showed similarities and differences between Ames dwarf mice and their normal siblings, indicating that calorie restriction and Ames dwarf mice exhibit their anti-aging effects through both independent and common mechanisms.
doi:10.3402/pba.v3i0.20833
PMCID: PMC3689900  PMID: 23799173
age-related pathology; Ames dwarf mice; calorie restriction; neoplastic disease; aging
13.  Thioredoxin 1 Overexpression Extends Mainly the Earlier Part of Life Span in Mice 
We examined the effects of increased levels of thioredoxin 1 (Trx1) on resistance to oxidative stress and aging in transgenic mice overexpressing Trx1 [Tg(TRX1)+/0]. The Tg(TRX1)+/0 mice showed significantly higher Trx1 protein levels in all the tissues examined compared with the wild-type littermates. Oxidative damage to proteins and levels of lipid peroxidation were significantly lower in the livers of Tg(TRX1)+/0 mice compared with wild-type littermates. The survival study demonstrated that male Tg(TRX1)+/0 mice significantly extended the earlier part of life span compared with wild-type littermates, but no significant life extension was observed in females. Neither male nor female Tg(TRX1)+/0 mice showed changes in maximum life span. Our findings suggested that the increased levels of Trx1 in the Tg(TRX1)+/0 mice were correlated to increased resistance to oxidative stress, which could be beneficial in the earlier part of life span but not the maximum life span in the C57BL/6 mice.
doi:10.1093/gerona/glr125
PMCID: PMC3210956  PMID: 21873593
Thioredoxin; Transgenic mouse; Oxidative stress; Protein carbonylation; Aging
14.  Myxomatous neoplasms in the perineal region of baboons 
Journal of medical primatology  2008;37(6):261-270.
Background
In baboons, Papio sp. neoplasms tend to affect the hematopoietic system most commonly, with rare documentation of myxomatous neoplasms. In contrast, women can develop myxomatous masses within deep peripelvic tissues with some frequency during their reproductive years.
Methods
We have identified and examined, retrospectively, myxomatous perineal masses in twelve female baboons within one research facility and compared their histopathologic, immunohistochemical and electron microscopic features to their human variants.
Results
Our results indicate that these myxomatous neoplasms, in humans and non-human primates, share common features.
Conclusion
Further research, particularly molecular genetic analysis, may be needed to identify the baboon as a true animal model for myxomatous perineal neoplasms.
doi:10.1111/j.1600-0684.2008.00293.x
PMCID: PMC3482000  PMID: 19017193
Aggressive angiomyxoma; angiomyofibroblastoma; cdk4; estrogen receptor; MDM2; progesterone receptor
15.  The Prevalence of Colonic Amyloidosis in Baboons. A 22-year Survey at a Large Primate Facility 
In vivo (Athens, Greece)  2008;22(6):725-727.
Background
Colonic amyloidosis has been previously reported in animals, however its prevalence rate has not yet been explored. The aim of the present work was to assess the prevalence of colonic amyloidosis at the Southwest National Primate Research Center since 1986.
Materials and Methods
Colonic amyloidosis was sought in autopsy material from baboons collected under the diagnosis of systemic amyloidosis.
Results
Between 1986 and 2007, a mean of 3,315 baboons per year (range 2,578–3,931) were housed at the Southwest National Primate Research Center. After examination, colonic amyloidosis was detected in 6 (6.8% ) of the 88 baboons with systemic amyloidosis, yielding a prevalence rate of 0.27 cases per year since 1986. Colonic amyloid deposits were found in the interstitial aspect of the lamina propria, often replacing normal mucosal crypts of Lieberkuhn.
Conclusion
It was observed that only 6.8% of animals with systemic amyloidosis examined between 1986 and 2007 developed colonic amyloidosis. The apparent natural resistance to colonic amyloidosis in baboons presenting systemic amyloidosis deserves to be further investigated.
PMCID: PMC3479647  PMID: 19180998
Amyloidosis; colon; baboon
16.  The Columnar-lined Mucosa in the Distal Esophagus. A Preliminary Study in Baboons 
In vivo (Athens, Greece)  2009;23(2):273-275.
Background
For anatomists, the cardia is a portion of the stomach. However, at the histological level, the cardiac mucosa, described as columnar-lined with mucus-producing glands (CLMMG), is for some pathologists part of the stomach (already present at birth) and for others a metaplastic change of the esophagus induced by gastro-esophageal reflux (GER).
Materials and Methods
The distal esophagus and the proximal stomach of 5 adult male baboons were removed en bloc at autopsy. The distance between the most distal part of the squamous epithelium of the esophagus and the first oxyntic fundic gastric gland (representing the entire CLMMG) was assessed using an ocular microscale.
Results
The length of the CLMMG varied from 1.2 mm to 12.4 mm. The CLMMG had replaced the squamous epithelium of the distal esophagus in all 5 baboons.
Discussion
Regurgitation with rumination is a natural physiological, daily, recurrent process in baboons that leads to GER. The luminal cytoplasmic vacuoles with neutral mucins contained in the columnar cells and the neutral mucins produced by the mucin glands buffer the low pH of the gastric juices that reflux into the distal esophagus. This protective action against the acid refluxate cannot be achieved by the squamous epithelium.
Conclusion
The results of this preliminary investigation suggest that in baboons, CLMMG is an adaptation process of the esophageal mucosal to the low pH microenvironment conveyed by protracted GER.
PMCID: PMC3479648  PMID: 19414413
Metaplasia; esophagus; reflux; baboons
17.  The Frequency of Gastric Amyloidosis in Baboons. A 22-year Survey at a Large Primate Facility 
In vivo (Athens, Greece)  2008;22(6):663-665.
Background
Systemic amyloidosis, caused by abnormal tissue accretion of plasma proteins, affects several organs of the gastrointestinal (GI) tract. Gastric amyloidosis, rare in humans, has only been reported once in animals.
Materials and Methods
Gastric amyloidosis was sought for in baboons with systemic amyloidosis.
Results
During the past 22 years (between January 1986 and January 2007) a mean of 3,315 baboons/year (range 2,578–3,931) were housed at the Southwest National Primate Research Center. Gastric amyloidosis was found in 9 (10.2%) of the 88 baboons having a diagnosis of systemic amyloidosis. Consequently, the prevalence of gastric amyloidosis occurring since 1986 at this facility was 0.41 baboons/year. Gastric amyloid deposits were found in the interstitial aspect of the lamina propria, replacing normal mucosal structures, in the submucosal stroma along the interface with the muscularis mucosae and in the interstitial tissue of submucosal lymphoid aggregates. In one of the animals, lumps of amyloid deposits with giant cells were found in the gastric mucosa.
Conclusion
Baboons with systemic amyloidosis usually show increasing frequency of amyloid deposits in the liver, large intestine, lymph nodes, spleen and the small intestine. We now demonstrate that it may also involve the stomach. Why certain organs of the GI tract in baboons are more susceptible than others to be affected by the process of systemic amyloidosis remains unexplained. The apparent natural resistance of the stomach of baboons to be affected by systemic amyloidosis deserves further investigation. The review of the literature indicates that this is only the second report on gastric amyloidosis in baboons.
PMCID: PMC3468905  PMID: 19180988
Amyloidosis; stomach; baboons
18.  The Frequency of Histological Features Mimicking Reflux Esophagitis: A Study in Non-human Primates 
In vivo (Athens, Greece)  2008;22(6):721-724.
Background
The frequency of histological changes mimicking those described for reflux esophagitis in humans was assessed in a cohort of non-human primates (NHP).
Materials and Methods
A total of 121 consecutive esophagi (from 103 baboons and 18 macaques) were classified according to Ismail-Beiji for reflux esophagitis in humans into grade 1, grade 2 and grade 3 esophagitis.
Results
Histological features compatible with reflux esophagitis were found in 28.2% of the baboons and in 22.2% of the macaques. Esophagitis grade 1 was more common in baboons (24%) than in macaques (6%), while esophagitis grade 2 was more common in macaques (17%) than in baboons (2%).
Conclusion
Although the prevalence of reflux esophagitis in man is at least 2%, only a fraction of patients demonstrate histological features consistent with grades 1, 2 or 3 esophagitis. Hence, the finding that 27% of a cohort of consecutive, unselected NHP had grades 1, 2 or 3 esophagitis at histology is remarkable. The possible causes for the difference between species, such as the oblique position often adopted by NHP during the gastric phase of digestion, the diet, regurgitation and subsequent re-ingestion, as well as the stress of NHP when kept in captivity, are reviewed.
PMCID: PMC3468915  PMID: 19180997
Esophagitis; reflux; non-human primates indent
19.  Polymerase Chain Reaction Detection of Trypanosoma cruzi in Macaca fascicularis Using Archived Tissues 
This study describes conventional and real-time polymerase chain reaction (PCR) methods developed to detect and quantify Trypanosoma cruzi DNA in cynomolgus monkeys (Macaca fascicularis) using formalin-fixed paraffin-embedded blocks archived for periods of up to 6 years. The highest concentration of T. cruzi DNA was found in the myocardium, urinary bladder, stomach, lymph node, adrenal gland, and colon. The concentration of T. cruzi DNA detected in cardiac tissues was 10–100-fold greater than found elsewhere; the mean concentrations of T. cruzi DNA in non-cardiac tissues were otherwise comparable. Trypanosoma cruzi DNA was amplified from cerebrum but not cerebellum or kidney. Successful use of DNA from formalin-fixed, paraffin-embedded blocks is important because most pathology laboratories routinely archive wax blocks. This archived resource can be used for further studies on the prevalence of this disease.
PMCID: PMC2740910  PMID: 19635875
20.  The Frequency of Glassy Cells in Barrett’s Mucosa: A Study in Baboons 
In vivo (Athens, Greece)  2009;23(6):925-927.
Background
Glands with glassy cells (GGCs) were recently found in 1.8% of patients showing Barrett’s mucosa in esophageal biopsies. Similar GGCs were more recently detected in a baboon having glandulo-metaplastic esophageal mucosa (GMEM). The aim was to assess the frequency of baboons with GMEM having GGCs.
Materials and Methods
GGCs were searched for in 68 consecutive baboons having GMEM. Sections were stained with H&E and with alcian blue (pH 2.5), to detect sialomucins in goblet cells (a marker of Barrett’s mucosa in GMEM).
Results
Two out of the 68 baboons with Barrett’s mucosa (2.9%) showed GGCs.
Conclusions
In similarity to humans, the Barrett’s mucosa in baboons may show GGCs. Although the significance of GGCs in baboons (and in humans) remains poorly understood, their presence might not be a fortuitous event but linked to the molecular events leading to the development of intestinal metaplasia in Barrett’s mucosa, a known pre-neoplastic mucosal change in the distal esophagus in humans.
PMCID: PMC3420813  PMID: 20023234
Nonhuman primate; pathology; disease; intestinal metaplasia
22.  Differential effects of enalapril and losartan on body composition and indices of muscle quality in aged male Fischer 344 × Brown Norway rats 
Age  2010;33(2):167-183.
The primary purpose of the present set of studies was to provide a direct comparison of the effects of the angiotensin-converting enzyme inhibitor enalapril and the angiotensin receptor blocker losartan on body composition, physical performance, and muscle quality when administered late in life to aged rats. Overall, enalapril treatment consistently attenuated age-related increases in adiposity relative to both placebo and losartan. The maximal effect was achieved after 3 months of treatment (between 24 and 27 months of age), at a dose of 40 mg/kg and was observed in the absence of any changes in physical activity, body temperature, or food intake. In addition, the reduction in fat mass was not due to changes in pathology given that enalapril attenuated age-related increases in tumor development relative to placebo- and losartan-treated animals. Both enalapril and losartan attenuated age-related decreases in grip strength, suggesting that changes in body composition appear dissociated from improvements in physical function and may reflect a differential impact of enalapril and losartan on muscle quality. To link changes in adiposity to improvements in skeletal muscle quality, we performed gene array analyses to generate hypotheses regarding cell signaling pathways altered with enalapril treatment. Based on these results, our primary follow-up pathway was mitochondria-mediated apoptosis of myocytes. Relative to losartan- and placebo-treated rats, only enalapril decreased DNA fragmentation and caspase-dependent apoptotic signaling. These data suggest that attenuation of the severity of skeletal muscle apoptosis promoted by enalapril may represent a distinct mechanism through which this compound improves muscle strength/quality.
doi:10.1007/s11357-010-9196-y
PMCID: PMC3127467  PMID: 21153712
Age-related adiposity; Body composition; Sarcopenia; Renin–angiotensin system; Physical function; Muscle quality
23.  Natural pathology of the Baboon (Papio spp.) 
Journal of medical primatology  2011;40(2):142-155.
Background
Baboons are useful animal models for biomedical research, but the natural pathology of the baboon is not as well defined as other non-human primates.
Methods
A computer search for all morphologic diagnoses from baboon necropsies at the Southwest National Primate Research Center was performed and included all the natural deaths and animals euthanized for natural causes.
Results
A total of 10,883 macroscopic or microscopic morphologic diagnoses in 4297 baboons were documented and are presented by total incidence, relative incidence by sex and age-group, and mean age of occurrence. The most common diagnoses in descending order of occurrence were hemorrhage, stillborn, amyloidosis, colitis, spondylosis, and pneumonia. The systems with the most diagnoses were the digestive, urogenital, musculoskeletal, and respiratory.
Conclusion
This extensive evaluation of the natural pathology of the baboon should be an invaluable biomedical research resource.
doi:10.1111/j.1600-0684.2010.00463.x
PMCID: PMC3167160  PMID: 21226714
diseases; monkey; non-human primates; pathology; spontaneous; survey
24.  Does Reduced IGF-1R Signaling in Igf1r+/− Mice Alter Aging? 
PLoS ONE  2011;6(11):e26891.
Mutations in insulin/IGF-1 signaling pathway have been shown to lead to increased longevity in various invertebrate models. Therefore, the effect of the haplo- insufficiency of the IGF-1 receptor (Igf1r+/−) on longevity/aging was evaluated in C57Bl/6 mice using rigorous criteria where lifespan and end-of-life pathology were measured under optimal husbandry conditions using large sample sizes. Igf1r+/− mice exhibited reductions in IGF-1 receptor levels and the activation of Akt by IGF-1, with no compensatory increases in serum IGF-1 or tissue IGF-1 mRNA levels, indicating that the Igf1r+/− mice show reduced IGF-1 signaling. Aged male, but not female Igf1r+/− mice were glucose intolerant, and both genders developed insulin resistance as they aged. Female, but not male Igf1r+/− mice survived longer than wild type mice after lethal paraquat and diquat exposure, and female Igf1r+/− mice also exhibited less diquat-induced liver damage. However, no significant difference between the lifespans of the male Igf1r+/− and wild type mice was observed; and the mean lifespan of the Igf1r+/− females was increased only slightly (less than 5%) compared to wild type mice. A comprehensive pathological analysis showed no significant difference in end-of-life pathological lesions between the Igf1r+/− and wild type mice. These data show that the Igf1r+/− mouse is not a model of increased longevity and delayed aging as predicted by invertebrate models with mutations in the insulin/IGF-1 signaling pathway.
doi:10.1371/journal.pone.0026891
PMCID: PMC3223158  PMID: 22132081
25.  Trypanosoma cruzi in non-human primates with a history of stillbirths: a retrospective study (Papio hamadryas spp.) and case report (Macaca fascicularis) 
Journal of medical primatology  2008;37(6):318-328.
Background
Congenital transmission of Trypanosoma cruzi has been described in humans and experimental work has been conducted with mice, but not with non-human primates (NHPs).
Methods
We conducted a retrospective study of female baboons (Papio hamadryas spp.) naturally seropositive or seronegative for T. cruzi with history of fetal loss, and we report a stillbirth in a cynomolgus macaque (Macaca fascicularis) with placental T. cruzi amastigotes.
Results
There were no differences in menstrual cycle parameters and the number of fetal losses between seropositive and seronegative baboons with history of fetal loss. The amount of parasite DNA detected using quantitative polymerase chain reaction (Q-PCR) in M. fascicularis placenta was within the range detected in infected baboon tissues.
Conclusions
There is no evidence that chronic maternal T. cruzi infection causes fetal loss in baboons. Q-PCR is a useful diagnostic tool to study archived NHP placentas.
doi:10.1111/j.1600-0684.2008.00302.x
PMCID: PMC3149842  PMID: 18671769
Baboon; macaque; placental lesions; reproductive performance; serology; trypanosomiasis

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