Mediterranean diet protects against a neuroinflammatory cortical transcriptome: Associations with brain volumetrics, peripheral inflammation, social isolation, and anxiety in nonhuman primates (Macaca fascicularis).

Mediterranean diets may be neuroprotective and prevent cognitive decline relative to Western diets, however the underlying biology is poorly understood. We assessed the effects of Western versus Mediterranean-like diets on RNAseq-generated transcriptional profiles in lateral temporal cortex and their relationships with longitudinal changes in neuroanatomy, circulating monocyte gene expression, and observations of social isolation and anxiety in 38 socially-housed, middle-aged female cynomolgus macaques (Macaca fascicularis). Diet resulted in differential expression of seven transcripts (FDR < 0.05). Cyclin dependent kinase 14 (CDK14), a proinflammatory regulator, was lower in the Mediterranean group. The remaining six transcripts [i.e., "lunatic fringe" (LFNG), mannose receptor C type 2 (MRC2), solute carrier family 3 member 2 (SLCA32), butyrophilin subfamily 2 member A1 (BTN2A1), katanin regulatory subunit B1 (KATNB1), and transmembrane protein 268 (TMEM268)] were higher in cortex of the Mediterranean group and generally associated with anti-inflammatory/neuroprotective pathways. KATNB1 encodes a subcomponent of katanin, important in maintaining microtubule homeostasis. BTN2A1 is involved in immunomodulation of γδ T-cells which have anti-neuroinflammatory and neuroprotective effects. CDK14, LFNG, MRC2, and SLCA32 are associated with inflammatory pathways. The latter four differentially expressed cortex transcripts were associated with peripheral monocyte transcript levels, neuroanatomical changes determined by MRI, and with social isolation and anxiety. These results provide important insights into the potential mechanistic processes linking diet, peripheral and central inflammation, and behavior. Collectively, our results provide evidence that, relative to Western diets, Mediterranean diets confer protection against peripheral and central inflammation which is reflected in preserved brain structure and socioemotional behavior. Ultimately, such protective effects may confer resilience to the development of neuropathology and associated disease.

Executive function mediates age-related variation in social integration in female vervet monkeys (Chlorocebus sabaeus).

In humans, social participation and integration wane with advanced age, a pattern hypothesized to stem from cognitive or physical decrements. Similar age-related decreases in social participation have been observed in several nonhuman primate species. Here, we investigated cross-sectional age-related associations between social interactions, activity patterns, and cognitive function in 25 group-living female vervets (a.k.a. African green monkeys, Chlorocebus sabaeus) aged 8-29 years. Time spent in affiliative behavior decreased with age, and time spent alone correspondingly increased. Furthermore, time spent grooming others decreased with age, but the amount of grooming received did not. The number of social partners to whom individuals directed grooming also decreased with age. Grooming patterns mirrored physical activity levels, which also decreased with age. The relationship between age and grooming time was mediated, in part, by cognitive performance. Specifically, executive function significantly mediated age's effect on time spent in grooming interactions. In contrast, we did not find evidence that physical performance mediated age-related variation in social participation. Taken together, our results suggest that aging female vervets were not socially excluded but decreasingly engaged in social behavior, and that cognitive deficits may underlie this relationship.

Mediterranean Diet Protects Against a Neuroinflammatory Cortical Transcriptome: Associations with Brain Volumetrics, Peripheral Inflammation, Social Isolation and Anxiety.

INTRODUCTION: Mediterranean diets may be neuroprotective and prevent cognitive decline relative to Western diets, however the underlying biology is poorly understood. METHODS: We assessed the effects of Western vs. Mediterranean-like diets on RNAseq generated transcriptional profiles in temporal cortex and their relationships with changes in MRI neuroimaging phenotypes, circulating monocyte gene expression, and observations of social isolation and anxiety in 38 socially-housed, middle-aged female cynomolgus macaques. RESULTS: Diet resulted in differential expression of seven transcripts (FDR<0.05). Cyclin dependent kinase 14 ( CDK14 ), a proinflammatory regulator, was lower in the Mediterranean group. The remaining six transcripts [i.e., "lunatic fringe" ( LFNG ), mannose receptor C type 2 ( MRC2 ), solute carrier family 3 member 2 ( SLCA32 ), butyrophilin subfamily 2 member A1 ( BTN2A1 ), katanin regulatory subunit B1 ( KATNB1 ), and transmembrane protein 268 ( TMEM268 )] were higher in cortex of the Mediterranean group and generally associated with anti-inflammatory/neuroprotective pathways. KATNB1 encodes a subcomponent of katanin, important in maintaining microtubule homeostasis. BTN2A1 is involved in immunomodulation of γδ T-cells which have anti-neuroinflammatory and neuroprotective effects. CDK14 , LFNG , MRC2, and SLCA32 are associated with inflammatory pathways. The latter four differentially expressed cortex transcripts were associated with monocyte transcript levels, changes in AD-relevant brain volumes determined by MRI over the course of the study, and social isolation and anxiety. CDK14 was positively correlated with monocyte inflammatory transcripts, changes in total brain, gray matter, cortical gray matter volumes, and time alone and anxious behavior, and negatively correlated with changes in total white matter and cerebrospinal fluid (CSF) volumes. In contrast, LFNG , MRC2 , and SLCA32 were negatively correlated with monocyte inflammatory transcripts and changes in total gray matter volume, and positively correlated with CSF volume changes, and SLCA32 was negatively correlated with time alone. DISCUSSION: Collectively, our results suggest that relative to Western diets, Mediterranean diets confer protection against peripheral and central inflammation which is reflected in preserved brain structure and behavior.

Demographic and hormonal evidence for menopause in wild chimpanzees.

Among mammals, post-reproductive life spans are currently documented only in humans and a few species of toothed whales. Here we show that a post-reproductive life span exists among wild chimpanzees in the Ngogo community of Kibale National Park, Uganda. Post-reproductive representation was 0.195, indicating that a female who reached adulthood could expect to live about one-fifth of her adult life in a post-reproductive state, around half as long as human hunter-gatherers. Post-reproductive females exhibited hormonal signatures of menopause, including sharply increasing gonadotropins after age 50. We discuss whether post-reproductive life spans in wild chimpanzees occur only rarely, as a short-term response to favorable ecological conditions, or instead are an evolved species-typical trait as well as the implications of these alternatives for our understanding of the evolution of post-reproductive life spans.

Lean muscle mass, not aggression, mediates a link between dominance rank and testosterone in wild male chimpanzees.

Testosterone promotes mating effort, which involves intraspecific aggression for males of many species. Therefore, males with higher testosterone levels are often thought to be more aggressive. For mammals living in multimale groups, aggression is hypothesized to link male social status (i.e. dominance rank) and testosterone levels, given that high status predicts mating success and is acquired partly through aggressive intragroup competition. In male chimpanzees, Pan troglodytes, dominance rank has been repeatedly linked to interindividual variation in testosterone levels, but evidence directly linking interindividual variation in testosterone and aggression is lacking. In the present study, we test both aggression levels and lean muscle mass, as measured by urinary creatinine, as links between dominance rank and testosterone levels in a large sample of wild male chimpanzees. Multivariate analyses indicated that dominance rank was positively associated with total rates of intragroup aggression, average urinary testosterone levels and average urinary creatinine levels. Testosterone was positively associated with creatinine levels but negatively associated with total aggression rates. Furthermore, mediation analyses showed that testosterone levels facilitated an association between dominance rank and creatinine levels. Our results indicate that (1) adult male chimpanzees with higher average testosterone levels are often higher ranking but not more aggressive than males with lower testosterone and (2) lean muscle mass links dominance rank and testosterone levels in Ngogo males. We assert that aggression rates are insufficient to explain links between dominance rank and testosterone levels in male chimpanzees and that other social variables (e.g. male-male relationship quality) may regulate testosterone's links to aggression.

The interactive effects of psychosocial stress and diet composition on health in primates.

Social disadvantage and diet composition independently impact myriad dimensions of health. They are closely entwined, as social disadvantage often yields poor diet quality, and may interact to fuel differential health outcomes. This paper reviews effects of psychosocial stress and diet composition on health in nonhuman primates and their implications for aging and human health. We examined the effects of social subordination stress and Mediterranean versus Western diet on multiple systems. We report that psychosocial stress and Western diet have independent and additive adverse effects on hypothalamic-pituitary-adrenal and autonomic nervous system reactivity to psychological stressors, brain structure, and ovarian function. Compared to the Mediterranean diet, the Western diet resulted in accelerated aging, nonalcoholic fatty liver disease, insulin resistance, gut microbial changes associated with increased disease risk, neuroinflammation, neuroanatomical perturbations, anxiety, and social isolation. This comprehensive, multisystem investigation lays the foundation for future investigations of the mechanistic underpinnings of psychosocial stress and diet effects on health, and advances the promise of the Mediterranean diet as a therapeutic intervention on psychosocial stress.

The evolution of the adolescent growth spurt: Urinary biomarkers of bone turnover in wild chimpanzees (Pan troglodytes).

Life history theory addresses how organisms balance development and reproduction. Mammals usually invest considerable energy into growth in infancy, and they do so incrementally less until reaching adult body size, when they shift energy to reproduction. Humans are unusual in having a long adolescence when energy is invested in both reproduction and growth, including rapid skeletal growth around puberty. Although many primates, especially in captivity, experience accelerated growth in mass around puberty, it remains unclear whether this represents skeletal growth. Without data on skeletal growth in nonhuman primates, anthropologists have often assumed the adolescent growth spurt is uniquely human, and hypotheses for its evolution have focused on other uniquely human traits. The lack of data is largely due to methodological difficulties of assessing skeletal growth in wild primates. Here, we use two urinary markers of bone turnover-osteocalcin and collagen-to study skeletal growth in a large, cross-sectional sample of wild chimpanzees (Pan troglodytes) at Ngogo, Kibale National Park, Uganda. For both bone turnover markers, we found a nonlinear effect of age, which was largely driven by males. For male chimpanzees, values for osteocalcin and collagen peaked at age 9.4 years and 10.8 years, respectively, which corresponds to early and middle adolescence. Notably, collagen values increased from 4.5 to 9 years, suggesting faster growth during early adolescence compared to late infancy. Biomarker levels plateaued at 20 years in both sexes, suggesting skeletal growth continues until then. Additional data, notably on females and infants of both sexes, are needed, as are longitudinal samples. However, our cross-sectional analysis suggests an adolescent growth spurt in the skeleton of chimpanzees, especially for males. Biologists should avoid claiming that the adolescent growth spurt is uniquely human, and hypotheses for the patterns of human growth should consider variation in our primate relatives.

Transcriptional profiles in olfactory pathway-associated brain regions of African green monkeys: Associations with age and Alzheimer's disease neuropathology.

Introduction: Olfactory impairment in older individuals is associated with an increased risk of Alzheimer's disease (AD). Characterization of age versus neuropathology-associated changes in the brain olfactory pathway may elucidate processes underlying early AD pathogenesis. Here, we report age versus AD neuropathology-associated differential transcription in four brain regions in the olfactory pathway of 10 female African green monkeys (vervet, Chlorocebus aethiops sabaeus), a well-described model of early AD-like neuropathology. Methods: Transcriptional profiles were determined by microarray in the olfactory bulb (OB), piriform cortex (PC), temporal lobe white matter (WM), and inferior temporal cortex (ITC). Amyloid beta (Aß) plaque load in parietal and temporal cortex was determined by immunohistochemistry, and concentrations of Aß42, Aß40, and norepinephrine in ITC were determined by enzyme-linked immuosorbent assay (ELISA). Transcriptional profiles were compared between middle-aged and old animals, and associations with AD-relevant neuropathological measures were determined. Results: Transcriptional profiles varied by brain region and age group. Expression levels of TRO and RNU4-1 were significantly lower in all four regions in the older group. An additional 29 genes were differentially expressed by age in three of four regions. Analyses of a combined expression data set of all four regions identified 77 differentially expressed genes (DEGs) by age group. Among these DEGs, older subjects had elevated levels of CTSB , EBAG9, LAMTOR3, and MRPL17, and lower levels of COMMD10 and TYW1B. A subset of these DEGs was associated with neuropathology biomarkers. Notably, CTSB was positively correlated with Aß plaque counts, Aß42:Aß40 ratios, and norepinephrine levels in all brain regions. Discussion: These data demonstrate age differences in gene expression in olfaction-associated brain regions. Biological processes exhibiting age-related enrichment included the regulation of cell death, vascular function, mitochondrial function, and proteostasis. A subset of DEGs was specifically associated with AD phenotypes. These may represent promising targets for future mechanistic investigations and perhaps therapeutic intervention.

Female reproduction and viral infection in a long-lived mammal.

For energetically limited organisms, life-history theory predicts trade-offs between reproductive effort and somatic maintenance. This is especially true of female mammals, for whom reproduction presents multifarious energetic and physiological demands. Here, we examine longitudinal changes in the gut virome (viral community) with respect to reproductive status in wild mature female chimpanzees Pan troglodytes schweinfurthii from two communities, Kanyawara and Ngogo, in Kibale National Park, Uganda. We used metagenomic methods to characterize viromes of individual chimpanzees while they were cycling, pregnant and lactating. Females from Kanyawara, whose territory abuts the park's boundary, had higher viral richness and loads (relative quantity of viral sequences) than females from Ngogo, whose territory is more energetically rich and located farther from large human settlements. Viral richness (total number of distinct viruses per sample) was higher when females were lactating than when cycling or pregnant. In pregnant females, viral richness increased with estimated day of gestation. Richness did not vary with age, in contrast to prior research showing increased viral abundance in older males from these same communities. Our results provide evidence of short-term physiological trade-offs between reproduction and infection, which are often hypothesized to constrain health in long-lived species.

Viruses associated with ill health in wild chimpanzees.

Viral infection is a major cause of ill health in wild chimpanzees (Pan troglodytes), but most evidence to date has come from conspicuous disease outbreaks with high morbidity and mortality. To examine the relationship between viral infection and ill health during periods not associated with disease outbreaks, we conducted a longitudinal study of wild eastern chimpanzees (P. t. schweinfurthii) in the Kanyawara and Ngogo communities of Kibale National Park, Uganda. We collected standardized, observational health data for 4 years and then used metagenomics to characterize gastrointestinal viromes (i.e., all viruses recovered from fecal samples) in individual chimpanzees before and during episodes of clinical disease. We restricted our analyses to viruses thought to infect mammals or primarily associated with mammals, discarding viruses associated with nonmammalian hosts. We found 18 viruses (nine of which were previously identified in this population) from at least five viral families. Viral richness (number of viruses per sample) did not vary by health status. By contrast, total viral load (normalized proportion of sequences mapping to viruses) was significantly higher in ill individuals compared with healthy individuals. Furthermore, when ill, Kanyawara chimpanzees exhibited higher viral loads than Ngogo chimpanzees, and males, but not females, exhibited higher infection rates with certain viruses and higher total viral loads as they aged. Post-hoc analyses, including the use of a machine-learning classification method, indicated that one virus, salivirus (Picornaviridae), was the main contributor to health-related and community-level variation in viral loads. Another virus, chimpanzee stool-associated virus (chisavirus; unclassified Picornavirales), was associated with ill health at Ngogo but not at Kanyawara. Chisavirus, chimpanzee adenovirus (Adenoviridae), and bufavirus (Parvoviridae) were also associated with increased age in males. Associations with sex and age are consistent with the hypothesis that nonlethal viral infections cumulatively reflect or contribute to senescence in long-lived species such as chimpanzees.

Urinary neopterin of wild chimpanzees indicates that cell-mediated immune activity varies by age, sex, and female reproductive status.

The study of free-living animal populations is necessary to understand life history trade-offs associated with immune investment. To investigate the role of life history strategies in shaping proinflammatory cell-mediated immune function, we analyzed age, sex, and reproductive status as predictors of urinary neopterin in 70 sexually mature chimpanzees (Pan troglodytes) at Ngogo, Kibale National Park, Uganda. In the absence of clinical signs of acute infectious disease, neopterin levels significantly increased with age in both male and female chimpanzees, as observed in humans and several other vertebrate species. Furthermore, males exhibited higher neopterin levels than females across adulthood. Finally, females with full sexual swellings, pregnant females, and post-reproductive females, the oldest individuals in our sample, exhibited higher neopterin levels than lactating females and cycling females without full swellings. Variation in females' neopterin levels by reproductive status is consistent with post-ovulatory and pregnancy-related immune patterns documented in humans. Together, our results provide evidence of ample variation in chimpanzee immune activity corresponding to biodemographic and physiological variation. Future studies comparing immune activity across ecological conditions and social systems are essential for understanding the life histories of primates and other mammals.

Demography, life-history trade-offs, and the gastrointestinal virome of wild chimpanzees.

In humans, senescence increases susceptibility to viral infection. However, comparative data on viral infection in free-living non-human primates-even in our closest living relatives, chimpanzees and bonobos (Pan troglodytes and P. paniscus)-are relatively scarce, thereby constraining an evolutionary understanding of age-related patterns of viral infection. We investigated a population of wild eastern chimpanzees (P. t. schweinfurthii), using metagenomics to characterize viromes (full viral communities) in the faeces of 42 sexually mature chimpanzees (22 males, 20 females) from the Kanyawara and Ngogo communities of Kibale National Park, Uganda. We identified 12 viruses from at least four viral families possessing genomes of both single-stranded RNA and single-stranded DNA. Faecal viromes of both sexes varied with chimpanzee age, but viral richness increased with age only in males. This effect was largely due to three viruses, salivirus, porprismacovirus and chimpanzee stool-associated RNA virus (chisavirus), which occurred most frequently in samples from older males. This finding is consistent with the hypothesis that selection on males for early-life reproduction compromises investment in somatic maintenance, which has delayed consequences for health later in life, in this case reflected in viral infection and/or shedding. Faecal viromes are therefore useful for studying processes related to the divergent reproductive strategies of males and females, ageing, and sex differences in longevity. This article is part of the theme issue 'Evolution of the primate ageing process'.

Corpse-directed play parenting by a sterile adult female chimpanzee.

The study of representational play in nonhuman primates, including chimpanzees (Pan troglodytes), provides interspecific perspectives on human cognitive development and evolution. A notable form of representational play in chimpanzees is play parenting, wherein parental behavior is directed at inanimate objects. Though observed in captivity, unambiguous examples of play parenting by wild chimpanzees are rare. Here, we report two cases from Ngogo in Kibale National Park, Uganda, in which a wild adult female chimpanzee (P. t. schweinfurthii) directed parental behaviors at corpses. Both cases involved the same adult female chimpanzee, aged 20-21 years. The first case was observed on 5 March 2016, and the play object was the corpse of a bushbaby (Galago thomasi); in the second case, observed on 6 May 2017, the play object was a recently deceased chimpanzee infant postmortally stolen from the mother. The chimpanzee possessed the first and second play objects for approximately 5.5 h and 1.8 h, respectively. In both cases, she performed a variety of maternal behaviors, including co-nesting, grooming, and dorsally carrying the play objects. In contrast to previous observations of play parenting in captivity, the play parent was a presumably sterile adult female, well beyond the average age of first birth. These observations contribute to the expanding literature on chimpanzee interactions with the corpses of both conspecifics and heterospecifics.

Social Network Predicts Exposure to Respiratory Infection in a Wild Chimpanzee Group.

Respiratory pathogens are expected to spread through social contacts, but outbreaks often occur quickly and unpredictably, making it challenging to simultaneously record social contact and disease incidence data, especially in wildlife. Thus, the role of social contacts in the spread of infectious disease is often treated as an assumption in disease simulation studies, and few studies have empirically demonstrated how pathogens spread through social networks. In July-August 2015, an outbreak of respiratory disease was observed in a wild chimpanzee community in Kibale National Park, Uganda, during an ongoing behavioral study of male chimpanzees, offering a rare opportunity to evaluate how social behavior affects individual exposure to socially transmissible diseases. From May to August 2015, we identified adult and adolescent male chimpanzees displaying coughs and rhinorrhea and recorded 5-m proximity data on males (N = 40). Using the network k-test, we found significant relationships between male network connectivity and the distribution of cases within the network, supporting the importance of short-distance contacts for the spread of the respiratory outbreak. Additionally, chimpanzees central to the network were more likely to display clinical signs than those with fewer connections. Although our analyses were limited to male chimpanzees, these findings underscore the value of social connectivity data in predicting disease outcomes and elucidate a potential evolutionary cost of being social.

Dominance rank and the presence of sexually receptive females predict feces-measured body temperature in male chimpanzees.

Quantifying the costs of mating is key for understanding life-history trade-offs. As a reflection of metabolic rate, body temperature is one metric for assaying these costs. However, conventional methods for measuring body temperature are invasive and unsuitable for the study of free-living populations of endangered species, including great apes. A promising proxy for body temperature is fecal temperature, the internal temperature of fecal deposits shortly following defecation. We validated this method with humans, finding that maximum fecal temperature is a reliable proxy for rectal temperature. We then applied this method to wild chimpanzees (Pan troglodytes schweinfurthii) at Ngogo, Kibale National Park, Uganda. We collected and analyzed 101 fecal temperature measurements from 43 adult chimpanzees (male: N = 28; female: N = 15). Chimpanzee fecal temperature ranged from 33.4 to 38.9 °C, with a mean of 35.8 °C. Although fecal temperature was not predicted by sex, age, or ambient temperature, male fecal temperature was 1.1 °C higher on days when sexually receptive females were present and was positively correlated with male dominance rank. Post hoc analyses showed that overall copulation rates, but not aggression rates, were positively correlated with fecal temperature, suggesting that sexual physiology and behavior best explain mating-related temperature variation. Together, these results indicate fecal temperature is a reliable proxy for core body temperature in large-bodied mammals, captures metabolic costs associated with male mating behavior, and represents a valuable noninvasive tool for biological field research.

Simultaneous outbreaks of respiratory disease in wild chimpanzees caused by distinct viruses of human origin.

Respiratory viruses of human origin infect wild apes across Africa, sometimes lethally. Here we report simultaneous outbreaks of two distinct human respiratory viruses, human metapneumovirus (MPV; Pneumoviridae: Metapneumovirus) and human respirovirus 3 (HRV3; Paramyxoviridae; Respirovirus, formerly known as parainfluenza virus 3), in two chimpanzee (Pan troglodytes schweinfurthii) communities in the same forest in Uganda in December 2016 and January 2017. The viruses were absent before the outbreaks, but each was present in ill chimpanzees from one community during the outbreak period. Clinical signs and gross pathologic changes in affected chimpanzees closely mirrored symptoms and pathology commonly observed in humans for each virus. Epidemiologic modelling showed that MPV and HRV3 were similarly transmissible (R0 of 1.27 and 1.48, respectively), but MPV caused 12.2% mortality mainly in infants and older chimpanzees, whereas HRV3 caused no direct mortality. These results are consistent with the higher virulence of MPV than HRV3 in humans, although both MPV and HRV3 cause a significant global disease burden. Both viruses clustered phylogenetically within groups of known human variants, with MPV closely related to a lethal 2009 variant from mountain gorillas (Gorilla beringei beringei), suggesting two independent and simultaneous reverse zoonotic origins, either directly from humans or via intermediary hosts. These findings expand our knowledge of human origin viruses threatening wild chimpanzees and suggest that such viruses might be differentiated by their comparative epidemiological dynamics and pathogenicity in wild apes. Our results also caution against assuming common causation in coincident outbreaks.