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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.

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.

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.

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.

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.

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.

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

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.

In many birds and mammals, the size and sex composition of litters can have important downstream effects for individual offspring. Primates are model organisms for questions of cooperation and conflict, but the factors shaping interactions among same-age siblings have been less-studied in primates because most species bear single young. However, callitrichines (marmosets, tamarins, and lion tamarins) frequently bear litters of two or more, thereby providing the opportunity to ask whether variation in the size and sex composition of litters affects development, survival, and reproduction. To investigate these questions, we compiled a large dataset of 9 species of callitrichines (n= 27,080 individuals; Callithrix geoffroyi, Callithrix jacchus, Cebuella pygmaea, Saguinus imperator, Saguinus oedipus, Leontopithecus chrysomelas, Leontopithecus chrysopygus, Leontopithecus rosalia, and Callimico goeldii) from zoo and laboratory populations spanning 80 years (1938 to 2018). Through this comparative approach, we found several lines of evidence that litter size and sex composition may impact fitness. Singletons have higher survivorship than litter-born peers and they significantly outperform litter-born individuals on two measures of reproductive performance. Further, for some species, individuals born in a mixed-sex litter outperform isosexually-born individuals (i.e., those born in all-male or all-female litters), suggesting that same-sex competition may limit reproductive performance. We also document several interesting demographic trends. All but one species (Cebuella pygmaea) has a male-biased birth sex ratio (BSR) with higher survivorship from birth to sexual maturity among females (although this was significant in only two species). Isosexual litters occurred at the expected frequency (with one exception: Cebuella pygmaea), unlike other animals, where isosexual litters are typically over-represented. Taken together, our results indicate a modest negative effect of same-age sibling competition on reproductive output in captive callitrichines. This study also serves to illustrate the value of zoo and laboratory records for biological inquiry.

Age-related neurodegeneration associated with Alzheimer’s (AD) disease begins in middle age, well before the onset of symptoms. Therefore, translational models to identify modifiable risk factors in middle-age are needed to understand etiology and identify therapeutic targets. Vervet monkeys (Chlorocebus aethiops sabaeus), like humans, naturally develop several risk factors for AD with age, including obesity, prediabetes, and hypertension. Furthermore, older vervets exhibit accumulation of amyloid and tauopathies, decreased brain volumes, and physical declines in gait speed, suggesting that these NHPs may be useful models of early AD-like neuropathology. Currently, we are investigating the extent to which cognitive and physical decline co-occur in 20 elder (mean age=23 years, ~equivalent to a human age of 80 years) and 10 middle-aged (mean age=11 years) females through assessments of physical performance, executive function, social cognition, and short-term memory. These measures are part of a larger study to integrate physical, social, and cognitive function with measures of body composition, metabolic profiles, CSF, blood, neuroimages, and neuropathology. While tests of social cognition and short-term memory are ongoing, assessments of executive function indicate that performance declines with age (N=26; p

Sampson et al. discuss the economic and societal value of graduate education, in particular in the USA.

Background Sexual differentiation in female mammals can be altered by the proximity of male littermates in utero, a phenomenon known as the intrauterine position effect (IUP). Among simian primates, callitrichines (marmosets and tamarins) are likely candidates for IUP, since they exhibit obligate dizygotic twinning and fetuses share extensive vascularization in utero. In this paper, we determined whether female reproductive parameters are altered by gestating with a male twin and evaluated changes in genes associated with anti-Müllerian and steroid hormones in twinning callitrichine primates. Methods We assessed the impact of gestation with male cotwins on reproductive performance and survivorship in female marmosets (Callithrix) and lion tamarins (Leontopithecus), contrasting measures for females gestated with one or more littermates (M+) or no male littermates (0M). We compared targeted coding regions for genes involved in steroidal and anti-Müllerian hormone mediation of sexual differentiation for representatives of twinning callitrichines (Callithrix, Saguinus, and Leontopithecus) with closely related New World primates that produce single births (Saimiri and Callimico). Results IUP effects in females were absent in female callitrichine primates: age at first ovulation, average litter size, and the proportion of stillborn infants, and lifetime survivorship did not differ between M+ and 0M females. We documented multiple nonsynonymous substitutions in genes associated with steroid synthesis, transport, and cellular action (SRD5A2, CYP19A1, SHBG, and AR) and with anti-Müllerian hormone (AMH and AMHR2) in callitrichines. In the only callitrichine to produce single infants (Callimico), two genes contained nonsynonymous substitutions relative to twinning callitrichines (CYP19A1 and AMRHR2); these substitutions were identical with nontwinning Saimiri and humans, suggesting a reversion to an ancestral sequence. Conclusions In spite of a shared placental vasculature with opposite-sex twins throughout embryonic and fetal development, female callitrichine primates gestated with a male cotwin exhibit no decrement in reproductive performance relative to females gestated with female cotwins. Hence, IUP effects on female reproduction in callitrichines are modest. We have identified mutations in candidate genes relevant for steroid hormone signaling and metabolism, and especially in AMH-related genes, that are likely to alter protein structure and function in the callitrichines. These mutations may confer protection for females from the masculinizing and defeminizing influences of gestating with a male cotwin. Electronic supplementary material The online version of this article (doi:10.1186/s13293-016-0081-y) contains supplementary material, which is available to authorized users.