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Abstract Background The objective of this study was to increase understanding of the complex interactions between diet, obesity, and the gut microbiome of adult female non-human primates (NHPs). Subjects consumed either a Western (n=15) or Mediterranean (n=14) diet designed to represent human dietary patterns for 31 months. Body composition was determined using CT, fecal samples were collected, and shotgun metagenomic sequencing was performed. Gut microbiome results were grouped by diet and adiposity. Results Diet was the main contributor to gut microbiome bacterial diversity. Adiposity within each diet was associated with subtle shifts in the proportional abundance of several taxa. Mediterranean diet-fed NHPs with lower body fat had a greater proportion of Lactobacillus animalis than their higher body fat counterparts. Higher body fat Western diet-fed NHPs had more Ruminococcus champaneliensis and less Bacteroides uniformis than their low body fat counterparts. Western diet-fed NHPs had significantly higher levels of Prevotella copri than Mediterranean diet NHPs. Western diet-fed subjects were stratified by P. copri abundance (P. copriHIGH versus P. copriLOW), which was not associated with adiposity. Overall, Western diet-fed animals in the P. copriHIGH group showed greater proportional abundance of B. ovatus, B. faecis, P. stercorea, P. brevis, and Faecalibacterium prausnitzii than those in the Western P. copriLOW group. Western diet P. copriLOW subjects had a greater proportion of Eubacterium siraeum. E. siraeum negatively correlated with P. copri proportional abundance regardless of dietary consumption. In the Western diet group, Shannon diversity was significantly higher in P. copriLOW when compared to P. copriHIGH subjects. Furthermore, gut E. siraeum abundance positively correlated with HDL plasma cholesterol indicating that those in the P. copriLOW population may represent a more metabolically healthy population. Untargeted metabolomics on urine and plasma from Western diet-fed P. copriHIGH and P. copriLOW subjects suggest early kidney dysfunction in Western diet-fed P. copriHIGH subjects. Conclusions In summary, the data indicate diet to be the major influencer of gut bacterial diversity. However, diet and adiposity must be considered together when analyzing changes in abundance of specific bacterial taxa. Interestingly, P. copri appears to mediate metabolic dysfunction in Western diet-fed NHPs.

Age-related neuropathology associated with sporadic Alzheimer's disease (AD) often develops well before the onset of symptoms. Given AD's long preclinical period, translational models are needed to identify early signatures of pathological decline.Using structural magnetic resonance imaging and cognitive assessments, we examined the relationships among age, cognitive performance, and neuroanatomy in 48 vervet monkeys (We found negative associations of age with cortical gray matter volume (Cortical gray matter diminishes with age in vervets in regions relevant to AD, which may increase risk of cognitive impairment. This study lays the groundwork for future investigations to test therapeutics to delay or slow pathological decline.

Mitochondrial dysfunction is evident in diseases affecting cognition and metabolism such as Alzheimer’s disease and type 2 diabetes. Human studies of brain mitochondrial function are limited to postmortem tissue, preventing the assessment of bioenergetics by respirometry. Here, we investigated the effect of two diets on mitochondrial bioenergetics in three brain regions: the prefrontal cortex (PFC), the entorhinal cortex (ERC), and the cerebellum (CB), using middle-aged nonhuman primates. Eighteen female cynomolgus macaques aged 12.3 ± 0.7 yr were fed either a Mediterranean diet that is associated with healthy outcomes or a Western diet that is associated with poor cognitive and metabolic outcomes. Average bioenergetic capacity within each brain region did not differ between diets. Distinct brain regions have different metabolic requirements related to their function and disease susceptibility. Therefore, we also examined differences in bioenergetic capacity between brain regions. Mitochondria isolated from animals fed a Mediterranean diet maintained distinct differences in mitochondrial bioenergetics between brain regions, whereas animals fed the Western diet had diminished distinction in bioenergetics between brain regions. Notably, fatty acid β-oxidation was not affected between regions in animals fed a Western diet. In addition, bioenergetics in animals fed a Western diet had positive associations with fasting blood glucose and insulin levels in PFC and ERC mitochondria but not in CB mitochondria. Altogether, these data indicate that a Western diet disrupts bioenergetic patterns across brain regions and that circulating blood glucose and insulin levels in Western-diet fed animals influence bioenergetics in brain regions susceptible to Alzheimer’s disease and type 2 diabetes. NEW & NOTEWORTHY We show that compared with cynomolgus macaques fed a Mediterranean diet, a Western diet resulted in diminished bioenergetic pattern between brain regions related to blood glucose and insulin levels, specifically in brain regions susceptible to neurodegeneration and diabetes. In addition, fatty acid metabolism not directly linked to the TCA cycle and glucose metabolism did not show differences in bioenergetics due to diet.

Dietary changes associated with industrialization substantially increase the prevalence of chronic diseases, such as obesity, type II diabetes, and cardiovascular disease, which are major contributors to the public health burden. The high prevalence of these chronic diseases is often attributed to an “evolutionary mismatch,” between human physiology and modern nutritional environments. In support of this idea, Western diets enriched with foods that were scarce throughout human evolutionary history (e.g., simple sugars and saturated fats) promote inflammation and disease relative to diets more akin to hunter-gatherer diets, such as a Mediterranean diet; however, the mechanisms linking dietary mismatch to inflammation and chronic disease are poorly understood. We used a macaque model and whole diet manipulations to evaluate one possible mechanism – inflammatory polarization of monocytes – that potentially leads to this evolutionary mismatch. After consuming a Western- or Mediterranean-like diet for 15 months, monocytes from Western diet consumers exhibited a more proinflammatory phenotype, with 40% of their genes differentially expressed (FDR

Aging across the Primate Order is poorly understood because ages of individuals are often unknown, there is a dearth of aged animals available for study, and because aging is best characterized by longitudinal studies which are difficult to carry out in long-lived species. The human population is aging rapidly, and advanced age is a primary risk factor for several chronic diseases and conditions that impact healthspan. As lifespan has increased, diseases and disorders of the central nervous system (CNS) have become more prevalent, and Alzheimer’s disease and related dementias have become epidemic. Non-human primate (NHP) models are key to understanding the aging primate CNS. This Special Issue presents a review of current knowledge about NHP CNS aging across the Primate Order. Similarities and differences to human aging, and their implications for the validity of NHP models of aging are considered. Topics include aging-related brain structure and function, neuropathologies, cognitive performance, social behavior and social network characteristics, and physical, sensory, and motor function. Challenges to primate CNS aging research are discussed. Together, this collection of articles demonstrates the value of studying aging in a breadth of NHP models to advance our understanding of human and nonhuman primate aging and healthspan.

Description, Multiplex single-synapse events from multiple regions of Alzheimer’s disease brain revealed new alterations unique to humans., Synaptic molecular characterization is limited for Alzheimer’s disease (AD). Our newly invented mass cytometry–based method, synaptometry by time of flight (SynTOF), was used to measure 38 antibody probes in approximately 17 million single-synapse events from human brains without pathologic change or with pure AD or Lewy body disease (LBD), nonhuman primates (NHPs), and PS/APP mice. Synaptic molecular integrity in humans and NHP was similar. Although not detected in human synapses, Aβ was in PS/APP mice single-synapse events. Clustering and pattern identification of human synapses showed expected disease-specific differences, like increased hippocampal pathologic tau in AD and reduced caudate dopamine transporter in LBD, and revealed previously unidentified findings including increased hippocampal CD47 and lowered DJ1 in AD and higher ApoE in AD with dementia. Our results were independently supported by multiplex ion beam imaging of intact tissue. This highlights the higher depth and breadth of insight on neurodegenerative diseases obtainable through SynTOF.

Age-related neurodegeneration characteristic of late-onset Alzheimer's disease (LOAD) begins in middle age, well before symptoms. Translational models to identify modifiable risk factors are needed to understand etiology and identify therapeutic targets. Here, we outline the evidence supporting the vervet monkey (Chlorocebus aethiops sabaeus) as a model of aging-related AD-like neuropathology and associated phenotypes including cognitive function, physical function, glucose handling, intestinal physiology, and CSF, blood, and neuroimaging biomarkers. This review provides the most comprehensive multisystem description of aging in vervets to date. This review synthesizes a large body of evidence that suggests that aging vervets exhibit a coordinated suite of traits consistent with early AD and provide a powerful, naturally occurring model for LOAD. Notably, relationships are identified between AD-like neuropathology and modifiable risk factors. Gaps in knowledge and key limitations are provided to shape future studies to illuminate mechanisms underlying divergent neurocognitive aging trajectories and to develop interventions that increase resilience to aging-associated chronic disease, particularly, LOAD.

Dual declines in gait speed and cognitive performance are associated with increased risk of developing dementia. Characterizing the patterns of such impairments therefore is paramount to distinguishing healthy from pathological aging. Nonhuman primates such as vervet/African green monkeys (Chlorocebus aethiops sabaeus) are important models of human neurocognitive aging, yet the trajectory of dual decline has not been characterized. We therefore (1) assessed whether cognitive and physical performance (i.e., gait speed) are lower in older aged animals; (2) explored the relationship between performance in a novel task of executive function (Wake Forest Maze Task—WFMT) and a well-established assessment of working memory (delayed response task—DR task); and (3) examined the association between baseline gait speed with executive function and working memory at 1-year follow-up. We found (1) physical and cognitive declines with age; (2) strong agreement between performance in the novel WFMT and DR task; and (3) that slow gait is associated with poor cognitive performance in both domains. Our results suggest that older aged vervets exhibit a coordinated suite of traits consistent with human aging and that slow gait may be a biomarker of cognitive decline. This integrative approach provides evidence that gait speed and cognitive function differ across the lifespan in female vervet monkeys, which advances them as a model that could be used to dissect relationships between trajectories of dual decline over time. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11357-021-00338-w.

Adolescent depression is a common and serious mental disorder with unique characteristics that are distinct from adult depression. The adult non-human primate stress-induced model of depressive-like behavior is an excellent model for the study of mechanisms; however, an adolescent nonhuman primate model is still lacking. Ten male adolescent cynomolgus monkeys were divided into a chronic unpredictable mild stress (CUMS, n = 5) group and a control (CON, n = 5) group by age and weight-matched pairs. The CUMS group was exposed to multiple unpredictable mild stressors for five cycles over 55 days. At baseline, there were no differences between CUMS and CON groups. At endpoint, the CUMS group demonstrated significantly higher depressive-like behavior (huddle posture), and significantly lower locomotion compared with the CON group. Furthermore, depressive-like behavior increased from baseline to endpoint in the CUMS group, but not changed in the CON group. In the attempt for apple test, the CUMS group made significantly fewer attempts for the apple than the CON group. In the human intruder test, the CUMS group showed significantly higher anxiety-like behaviors in the stare phase than the CON group. Hair cortisol level was significantly higher in the CUMS group than the CON group at endpoint, and was also elevated from baseline to endpoint. Metabolic profiling of plasma at endpoint identified alterations in metabolite pathways which overlapped with those of adolescent depression patients. CUMS can induce depressive-like and anxiety-like behaviors, hypercortisolemia, and metabolic perturbations in adolescent cynomolgus monkeys. This is a promising model to study the mechanisms underlying adolescent depression.

Dietary composition is associated with the differential prevalence of psychiatric disorders; the Western diet confers increased risk, while the Mediterranean diet appears to reduce risk. In nonhuman primates, anxiety-like behaviors and social isolation have been linked to both Western diet consumption and increased inflammatory disease risk, and recent evidence suggests that diet composition may affect immune system function in part through its effects on behavior. This is particularly important in the context of the global COVID-19 pandemic in which social isolation has been associated with disease. Here, we examined the effects of Western- and Mediterranean-like diets on social behavior in a randomized, 34-month preclinical trial in middle-aged female cynomolgus macaques (Macaca fascicularis). Diet induced rapid and persistent changes in a suite of behaviors. After just three months of experimental diet consumption, a composite measure of diet-altered behavior (DAB) significantly differed between the two diets (p = 0.014) and remained different throughout the 24-month experimental observation period (p = 2.2 × 10−8). Monkeys fed the Western diet spent more time alone (FDR = 4.4 × 10−5) and displayed more anxiety behavior (FDR = 0.048), whereas monkeys fed the Mediterranean diet spent more time resting (FDR = 0.0013), attentive (FDR = 0.017), and in body contact with groupmates (FDR = 4.1 × 10−8). These differences were largely due to changes in behavior of animals fed the Mediterranean diet, while Western-diet-fed-animals exhibited similar behaviors compared to the eight-month baseline period, during which all monkeys consumed a common laboratory diet. These observations provide experimental support in a nonhuman primate model, demonstrating a potential therapeutic benefit of the Mediterranean diet consumption to reduce social isolation and anxiety and thus mitigate social isolation-associated disorders that often accompany illness and disability.

Chronic psychosocial stress is associated with increased risk of many chronic diseases including type 2 diabetes mellitus. However, it is difficult to establish a causal relationship between stress and diabetes in human studies because stressors often are self-reported and may be distant in time from metabolic consequences. Macaques are useful models of the effects of chronic psychosocial stress on health and may develop obesity and diabetes similar to human beings. Thus, we studied the relationships between social subordination stress – a well-validated psychological stressor in macaques – and body composition and carbohydrate metabolism in socially housed, middle-aged female cynomolgus monkeys (Macaca fascicularis; n=42). Following an 8-week baseline phase, the monkeys were fed a Western diet for 36 months (about equivalent to 10 human years). Social status was determined based on the outcomes of agonistic interactions ([Formula: see text] observation hours/monkey). Phenotypes collected included plasma cortisol, body composition, circulating markers of glucose metabolism, activity levels, and heart rate variability measured as RMSSD (root of mean square of successive differences) and SDDN (standard deviation of beat to beat interval) after 1.5- and 3-years on diet. Mixed model analyses of variance revealed that aggression received, submissions sent, and cortisol were higher, and RMSSD and SDNN were lower in subordinates than dominants (social status: p 100 mg/dl) incidence was significantly higher in subordinates (23%) than dominants (0%) (Fisher’s exact test, p

INTRODUCTIONAssociations between diet, psychosocial stress, and neurodegenerative disease, including Alzheimer’s disease (AD), have been reported, but causal relationships are difficult to determine in human studies.METHODSWe used structural magnetic resonance imaging in a well-validated nonhuman primate model of AD-like neuropathology to examine the longitudinal effects of diet (Mediterranean versus Western) and social subordination stress on brain anatomy, including global volumes, cortical thicknesses and volumes, and twenty individual regions of interest (ROIs).RESULTSWestern diet resulted in greater cortical thicknesses, total brain volumes and gray matter, and diminished cerebrospinal fluid and white matter volumes. Socially stressed subordinates had smaller whole brain volumes but larger ROIs relevant to AD than dominants.DISCUSSIONThe observation of increased size of AD-related brain areas is consistent with similar reports of mid-life volume increases predicting increased AD risk later in life. While the biological mechanisms underlying the findings require future investigation, these observations suggest that Western diet and psychosocial stress instigate pathologic changes that increase risk of AD-associated neuropathologies, whereas Mediterranean diet may protect the brain.RESEARCH IN CONTEXTSystematic review: The authors reviewed the literature with PubMed and Google Scholar and found a number of publications which are cited that suggest that AD pathogenesis begins well before the onset of symptoms.Interpretation: Our findings support the hypothesis that Western diet and psychosocial stress may instigate neuroinflammatory responses that increase risk of later developing AD-like neuropathologies, whereas the structural stasis in the Mediterranean diet group may represent a resilient phenotype.Future directions: The manuscript serves as a critical first step in describing risk and resilient phenotypes during middle age in a nonhuman primate model of AD-like neuropathology. This report lays the groundwork for ongoing efforts to determine whether neuroinflammatory profiles differed across diet and stress groups. Future studies should aim to understand the temporal emergence of functional disparities associated with the changes in brain structure observed here.HIGHLIGHTSGlobal brain volumes changed in response to Western, but not Mediterranean, diet.Western diet increased cortical thickness in multiple regions relevant to AD.Mediterranean diet did not alter cortical thicknesses relevant to AD.Brain regions associated with AD risk differed between low and high stress monkeys.Psychosocial stress may modulate the effects of diet on the brain.

OBJECTIVES: Poor diet and obesity often go hand-in-hand and are difficult to discern which variable is the major driver of the gut microbiome. The objective of this study was to determine the impact of obesity within dietary exposures on the gut microbiome and metabolic parameters using a non-human primate model. METHODS: Female M. fasicularis monkeys were fed a Western or Mediterranean diet for 2.5 years. We performed metagenomics sequencing on fecal samples obtained at 26 months. DNA was isolated from feces using Qiagen PowerSoil DNA extraction kit and metagenomics sequencing was performed for multikingdom microbiome analysis. DEXA scans for body adiposity and metabolic profiling were measured in each subject before the end of the study. Subjects were grouped by body fat composition (Lean (≤10% body fat) or Overweight/Obese (≥20% body fat)) and the impact of diet and adiposity was determine on the gut microbiome. Gut microbiota populations were correlated with metabolic parameters. RESULTS: Diet is the main determinant on gut microbiome α-diversity. Obesity had no significant outcome on Shannon diversity. Obesity within each dietary pattern can influence certain gut microbes. Lean Mediterranean diet-fed animals had significantly higher L. animals and C. comes that overweight animals fed the same diet. Obese Western diet-fed animals displayed elevated proportional abundance of S. infantarius and R. chanpaneliensis that lean Western diet-fed animals. Independent of adiposity, Western diet consumption lead to two distinct microbiome populations; P. copri high and P. copri low. P. copri(HIGH) displayed reduced α-diversity, increased abundance of other Prevotella species (P. stercorea, P. brevis, and P. bryantii), and increased F. prausnitzii. P. copri negatively correlated with α-diversity. P. copri(LOW) displayed increased proportional abundance of E. siraeum. Gut E. siraeum populations positively correlated with plasma HDL cholesterol levels. CONCLUSIONS: Our data indicates that diet is a potent regulator of the gut microbiome, while body adiposity can subtly shift specific gut microbiota taxa within subjects fed a specific dietary pattern. Moreover, our data indicates at a sub-group of metabolically healthier subjects on a Western diet characterized by low P. copri microbiota abundance. FUNDING SOURCES: NIH and DOD BCRP.

BACKGROUND: The social environment shapes human health, producing strong relationships between social factors, disease risk, and survival. The strength of these links has drawn attention from researchers in both the social and natural sciences, who share common interests in the biological processes that link the social environment to disease outcomes and mortality risk. Social scientists are motivated by an interest in contributing to policy that improves human health. Evolutionary biologists are interested in the origins of sociality and the determinants of Darwinian fitness. These research agendas have now converged to demonstrate strong parallels between the consequences of social adversity in human populations and in other social mammals, at least for the social processes that are most analogous between species. At the same time, recent studies in experimental animal models confirm that socially induced stress is, by itself, sufficient to negatively affect health and shorten life span. These findings suggest that some aspects of the social determinants of health—especially those that can be modeled through studies of direct social interaction in nonhuman animals— have deep evolutionary roots. They also present new opportunities for studying the emergence of social disparities in health and mortality risk. ADVANCES: The relationship between the social environment and mortality risk has been known in humans for some time, but studies in other social mammals have only recently been able to test for the same general phenomenon. These studies reveal that measures of social integration, social support, and, to a lesser extent, social status independently predict life span in at least four different mammalian orders. Despite key differences in the factors that structure the social environment in humans and other animals, the effect sizes that relate social status and social integration to natural life span in other mammals align with those estimated for social environmental effects in humans. Also like humans, multiple distinct measures of social integration have predictive value, and in the taxa examined thus far, social adversity in early life is particularly tightly linked to later-life survival. Animal models have also been key to advancing our understanding of the causal links between social processes and health. Studies in laboratory animals indicate that socially induced stress has direct effects on immune function, disease susceptibility, and life span. Animal models have revealed pervasive changes in the response to social adversity that are detectable at the molecular level. Recent work a. in mice has also shown that socially induced stress shortens natural life spans owing to multiple causes, including atherosclerosis. This result echoes those in humans, in which social adversity predicts increased mortality risk from almost all major causes of death. OUTLOOK: Although not all facets of the social determinants of health in humans can be effectively modeled in other social mammals, the strong evidence that some of these determinants are shared argues that comparative studies should play a frontline role in the effort to understand them. Expanding the set of species studied in nature, as well as the range of human populations in which the social environment is well characterized, should be a priority. Such studies have high potential to shed light on the pathways that connect social experience to life course outcomes as well as the evolutionary logic that accounts for these effects. Studies that draw on the power and tools afforded by laboratory model organisms are also crucial because of their potential for identifying causal links. Important research directions include understanding the predictors of interindividual and intersocietal differences in response to social adversity, testing the efficacy of potential interventions, and extending research on the physiological signatures of social gradients to the brain and other tissues. Path-breaking studies in this area will not only integrate results from different disciplines but also involve cross-disciplinary efforts that begin at study conception and design.

Introduction Nonhuman primates may serve as excellent models of sporadic age-associated brain β-amyloid deposition and Alzheimer's disease pathologic changes. We examined whether a vervet nonhuman primate model recapitulated pathologic, physiologic, and behavioral features of early Alzheimer's disease. Methods Nine middle-aged (mean = 11.2 years) and nine aged (mean = 21.7 years) female vervet/African green monkeys underwent cerebrospinal fluid collection, gait speed measurement, and neuroimaging before neuropathologic assessment. Results β-amyloid plaques were identified in all aged vervets and paired helical filament tau immunoreactivity was observed in all animals. Cerebrospinal fluid β-amyloid42 and gait speed correlated negatively with age and plaque density. Greater plaque and paired helical filament tau burden predicted reduced volumes and CMRg in several brain regions. Discussion We observed a coordinated set of relationships among neuropathologic, cerebrospinal fluid, imaging, and behavioral modalities consistent with early Alzheimer's disease. Our results support future use of the vervet model to explore disease mechanisms, biomarkers, and novel therapeutic strategies.

Summary: Recent identification of a mammary gland-specific microbiome led to studies investigating bacteria populations in breast cancer. Malignant breast tumors have lower Lactobacillus abundance compared with benign lesions, implicating Lactobacillus as a negative regulator of breast cancer. Diet is a main determinant of gut microbial diversity. Whether diet affects breast microbiome populations is unknown. In a non-human primate model, we found that consumption of a Western or Mediterranean diet modulated mammary gland microbiota and metabolite profiles. Mediterranean diet consumption led to increased mammary gland Lactobacillus abundance compared with Western diet-fed monkeys. Moreover, mammary glands from Mediterranean diet-fed monkeys had higher levels of bile acid metabolites and increased bacterial-processed bioactive compounds. These data suggest that diet directly influences microbiome populations outside the intestinal tract in distal sites such as the mammary gland. Our study demonstrates that diet affects the mammary gland microbiome, establishing an alternative mechanistic pathway for breast cancer prevention. : Using a non-human primate model of women’s health, Shively et al. demonstrate that diet plays a critical role in determining microbiota populations in tissues outside the gut, such as the mammary gland. These microbial populations modulate localized bile acid and bacterial-modified metabolites to potentially influence anticancer signaling pathways. Keywords: breast, mammary gland, diet, microbiome, bile acid, hippurate, oxidative stress

Introduction Depressive symptoms (DS) in humans are associated with decreased resting state vagal activity, but sex seems to moderate this association. Recently, in human females DS have been associated with greater or similar cardiac vagal activity compared to men in both, clinical and non-clinical samples. A previously validated animal model of behavioral depression was used in the present study to investigate the association of DS and cardiac vagal activity in non-human primates. Methods The root mean square of successive differences between adjacent heart beats (RMSSD) was used as an indicator of vagally-mediated heart rate variability in 24 h heart rate recordings collected via telemetry in 42 adult female cynomolgus monkeys (Macaca fascicularis). Hierarchical regression models were used to estimate differences in RMSSD comparing monkeys with and without DS. To capture circadian variation patterns of RMSSD, additional quadratic, cubic and quartic terms of hour were added. Results Monkeys showing behavioral DS had higher overall 24-h RMSSD. The interaction term of daytime with DS and polynomials of hour contributed significantly to the variance across models. Conclusions This is the first study investigating the association of DS and 24 h cardiac vagal control in female non-human primates. Results replicate existing human studies showing higher cardiac vagal control in behavioral depressed vs. non-depressed female monkeys.

Objective Atherosclerosis developed during premenopausal years predicts postmenopausal atherosclerosis burden. Selective serotonin reuptake inhibitor (SSRI) antidepressants, recently approved for hot flushes, have been associated with increased ischemic stroke risk in several observational studies; however, effects on carotid artery atherosclerosis, a strong predictor of future vascular events, are unknown. Methods The effects of chronic administration of a commonly prescribed SSRI, sertraline HCl, on atherosclerosis in the carotid artery was assessed in a placebo-controlled, longitudinal, randomized study of premeonopausal depressed and nondepressed cynomolgus monkeys (Macaca fascicularis; n = 42). Physiologic and behavioral phenotypes were evaluated at baseline and after 18 months of oral sertraline (20 mg/kg, n = 21) or placebo (n = 21). Carotid artery atherosclerosis was measured post mortem via histomorphometry. Results Atherosclerosis extent in the right common carotid artery, on average, was 60% greater in sertraline-treated depressed monkeys compared with all other groups (P = 0.028). The results of linear regression analyses suggested that sertraline and depression effects on atherosclerosis were not mediated by their effects on behavioral and physiological risk factors. Conclusions These findings suggest that chronic SSRI treatment is associated with the progression of carotid artery atherosclerosis, which may increase the risk for future vascular events, particularly in depressed women. The underlying mechanism remains to be determined, but does not appear to be related to SSRI effects on traditional cardiovascular risk factors.

Diet may influence the risk for cognitive decline and neurodegenerative disorders, including Alzheimer’s disease (AD), but these relationships are difficult to study in humans. Cynomolgus macaques (Macaca fascicularis) are appropriate models for investigations of diet effects on the brain because, like humans, they are omnivorous, have complex central nervous systems, are susceptible to diet-induced diseases, and accumulate amyloid and tauopathies with age. Using structural magnetic resonance imaging, we examined diet effects on brain anatomy by measuring thickness and volume of several areas relevant to AD in 38 middle-aged females, at baseline and after Mediterranean or Western diet consumption for 36 months (equivalent to a 9-year follow-up in humans). Using repeated measures analysis, cortical thicknesses generally increased in the Western diet group. Western diets also resulted in increases in total brain volume and cortical gray matter and decreases in cerebrospinal fluid, white matter, and deep gray matter (striatum and thalamus) (all p’s≤0.05). In contrast, thicknesses and volumes generally remained unchanged in animals consuming Mediterranean diets. Taken together, these findings demonstrate that Western diets induce widespread structural shifts which may increase risk of cognitive decline and neuropathology, whereas Mediterranean diets may exert a stabilizing influence on the brain. This study provides important insights about the significance of diet on brain structure and lays the groundwork for future investigations to uncover the molecular underpinnings of diet-induced changes in the brain. Mediterranean diet may protect against structural changes in brain that occur with age in those consuming a Western diet.

BackgroundWestern diets are associated with increased incidences of obesity, hypertension, diabetes, and hypercholesterolemia, whereas Mediterranean diets, richer in polyphenols, monounsaturated fats, fruits, vegetables, poultry, and fish, appear to have cardiometabolic health benefits. Previous work has included population-based studies with limited evidence for causation or animal studies focused on single macro- or micronutrients; therefore, primate animal models provide an opportunity to determine potential mechanisms underlying the effects of dietary patterns on health and disease.ObjectiveThe aim of this study was to determine the effects of whole dietary patterns, either a Western or Mediterranean diet, on skeletal muscle mitochondrial bioenergetics in cynomolgus macaques.MethodsIn this study, 22 adult female cynomolgus macaques (∼11-14 y by dentition) were fed either a Western or Mediterranean diet for 30 mo. The Western diet was designed to mimic the diet of a middle-aged American woman and the Mediterranean diet included key aspects of Mediterranean diets studied in humans, such as plant-based proteins and fat, complex carbohydrates, and fiber. Diets were matched on macronutrient composition (16% protein, 54% carbohydrate, and 31% fat) and cholesterol content. Skeletal muscle was collected for high-resolution respirometry, citrate synthase activity, and western blot measurements. Pearson correlation analysis between respirometry measures and measures of carbohydrate metabolism was also performed.ResultsWe found that consumption of a Western diet resulted in significantly higher mitochondrial respiration with fatty acid oxidation (FAO) (53%), FAO+complex I (52%), complex I+II (31%), max electron transport system (ETS) (31%), and ETS rotenone sensitive (31%) than did consumption of a Mediterranean diet. In addition, measures of respiration in response to fatty acids were significantly and positively correlated with both insulin resistance and plasma insulin concentrations.ConclusionsThis study highlights the importance of dietary composition in mitochondrial bioenergetics and that diet can influence skeletal muscle mitochondrial respiration independently of other factors such as macronutrient composition.