ABSTRACT
Phenotypic aging is ubiquitous across mammalian species, suggesting shared underlying mechanisms of aging. Aging is linked to molecular changes to DNA methylation and gene expression, and environmental factors, such as severe external challenges or adversities, can moderate these age-related changes. Yet, it remains unclear whether environmental adversities affect gene regulation via the same molecular pathways as chronological, or 'primary', aging. Investigating molecular aging in naturalistic animal populations can fill this gap by providing insight into shared molecular mechanisms of aging and the effects of a greater diversity of environmental adversities - particularly those that can be challenging to study in humans or laboratory organisms. Here, we characterised molecular aging - specifically, CpG methylation - in a sample of free-ranging rhesus macaques living off the coast of Puerto Rico (n samples = 571, n individuals = 499), which endured a major hurricane during our study. Age was associated with methylation at 78,661 sites (31% of all sites tested). Age-associated hypermethylation occurred more frequently in areas of active gene regulation, while hypomethylation was enriched in regions that show less activity in immune cells, suggesting these regions may become de-repressed in older individuals. Age-associated hypomethylation also co-occurred with increased chromatin accessibility while hypermethylation showed the opposite trend, hinting at a coordinated, multi-level loss of epigenetic stability during aging. We detected 32,048 CpG sites significantly associated with exposure to a hurricane, and these sites overlapped age-associated sites, most strongly in regulatory regions and most weakly in quiescent regions. Together, our results suggest that environmental adversity may contribute to aging-related molecular phenotypes in regions of active gene transcription, but that primary aging has specific signatures in non-regulatory regions.
ABSTRACT
Humans exhibit sex differences in the prevalence of many neurodevelopmental disorders and neurodegenerative diseases. Here, we generated one of the largest multi-brain-region bulk transcriptional datasets for the rhesus macaque and characterized sex-biased gene expression patterns to investigate the translatability of this species for sex-biased neurological conditions. We identify patterns similar to those in humans, which are associated with overlapping regulatory mechanisms, biological processes, and genes implicated in sex-biased human disorders, including autism. We also show that sex-biased genes exhibit greater genetic variance for expression and more tissue-specific expression patterns, which may facilitate rapid evolution of sex-biased genes. Our findings provide insights into the biological mechanisms underlying sex-biased disease and support the rhesus macaque model for the translational study of these conditions.
Subject(s)
Brain , Macaca mulatta , Sex Characteristics , Transcriptome , Animals , Macaca mulatta/genetics , Brain/metabolism , Female , Male , Humans , Evolution, MolecularABSTRACT
OBJECTIVES: Estimation of body mass from skeletal metrics can reveal important insights into the paleobiology of archeological or fossil remains. The standard approach constructs predictive equations from postcrania, but studies have questioned the reliability of traditional measures. Here, we examine several skeletal features to assess their accuracy in predicting body mass. MATERIALS AND METHODS: Antemortem mass measurements were compared with common skeletal dimensions from the same animals postmortem, using 115 rhesus macaques (male: n = 43; female: n = 72). Individuals were divided into training (n = 58) and test samples (n = 57) to build and assess Ordinary Least Squares or multivariate regressions by residual sum of squares (RSS) and AIC weights. A leave-one-out approach was implemented to formulate the best fit multivariate models, which were compared against a univariate and a previously published catarrhine body-mass estimation model. RESULTS: Femur circumference represented the best univariate model. The best model overall was composed of four variables (femur, tibia and fibula circumference and humerus length). By RSS and AICw, models built from rhesus macaque data (RSS = 26.91, AIC = -20.66) better predicted body mass than did the catarrhine model (RSS = 65.47, AIC = 20.24). CONCLUSION: Body mass in rhesus macaques is best predicted by a 4-variable equation composed of humerus length and hind limb midshaft circumferences. Comparison of models built from the macaque versus the catarrhine data highlight the importance of taxonomic specificity in predicting body mass. This paper provides a valuable dataset of combined somatic and skeletal data in a primate, which can be used to build body mass equations for fragmentary fossil evidence.
Subject(s)
Macaca mulatta , Animals , Macaca mulatta/anatomy & histology , Female , Male , Anthropology, Physical/methods , Body Weight , Bone and Bones/anatomy & histology , Humerus/anatomy & histologyABSTRACT
OBJECTIVES: Interpretations of the primate and human fossil record often rely on the estimation of somatic dimensions from bony measures. Both somatic and skeletal variation have been used to assess how primates respond to environmental change. However, it is unclear how well skeletal variation matches and predicts soft tissue. Here, we empirically test the relationship between tissues by comparing somatic and skeletal measures using paired measures of pre- and post-mortem rhesus macaques from Cayo Santiago, Puerto Rico. MATERIALS AND METHODS: Somatic measurements were matched with skeletal dimensions from 105 rhesus macaque individuals to investigate paired signals of variation (i.e., coefficients of variation, sexual dimorphism) and bivariate codependence (reduced major axis regression) in measures of: (1) limb length; (2) joint breadth; and (3) limb circumference. Predictive models for the estimation of soft tissue dimensions from skeletons were built from Ordinary Least Squares regressions. RESULTS: Somatic and skeletal measurements showed statistically equivalent coefficients of variation and sexual dimorphism as well as high epiphyses-present ordinary least square (OLS) correlations in limb lengths (R2 >0.78, 0.82), joint breadths (R2 >0.74, 0.83) and, to a lesser extent, limb circumference (R2 >0.53, 0.68). CONCLUSION: Skeletal measurements are good substitutions for somatic values based on population signals of variation. OLS regressions indicate that skeletal correlates are highly predictive of somatic dimensions. The protocols and regression equations established here provide a basis for reliable reconstruction of somatic dimension from catarrhine fossils and validate our ability to compare or combine results of studies based on population data of either hard or soft tissue proxies.
Subject(s)
Bone and Bones , Macaca mulatta , Animals , Macaca mulatta/anatomy & histology , Female , Male , Puerto Rico , Bone and Bones/anatomy & histology , Anthropology, Physical , Sex Characteristics , Extremities/anatomy & histologyABSTRACT
Increasing age is associated with dysregulated immune function and increased inflammation-patterns that are also observed in individuals exposed to chronic social adversity. Yet we still know little about how social adversity impacts the immune system and how it might promote age-related diseases. Here, we investigated how immune cell diversity varied with age, sex and social adversity (operationalized as low social status) in free-ranging rhesus macaques. We found age-related signatures of immunosenescence, including lower proportions of CD20 + B cells, CD20 + /CD3 + ratio, and CD4 + /CD8 + T cell ratio - all signs of diminished antibody production. Age was associated with higher proportions of CD3 + /CD8 + Cytotoxic T cells, CD16 + /CD3- Natural Killer cells, CD3 + /CD4 + /CD25 + and CD3 + /CD8 + /CD25 + T cells, and CD14 + /CD16 + /HLA-DR + intermediate monocytes, and lower levels of CD14 + /CD16-/HLA-DR + classical monocytes, indicating greater amounts of inflammation and immune dysregulation. We also found a sex-dependent effect of exposure to social adversity (i.e., low social status). High-status males, relative to females, had higher CD20 + /CD3 + ratios and CD16 + /CD3 Natural Killer cell proportions, and lower proportions of CD8 + Cytotoxic T cells. Further, low-status females had higher proportions of cytotoxic T cells than high-status females, while the opposite was observed in males. High-status males had higher CD20 + /CD3 + ratios than low-status males. Together, our study identifies the strong age and sex-dependent effects of social adversity on immune cell proportions in a human-relevant primate model. Thus, these results provide novel insights into the combined effects of demography and social adversity on immunity and their potential contribution to age-related diseases in humans and other animals.
Subject(s)
HLA-DR Antigens , Social Alienation , Male , Female , Animals , Humans , Macaca mulatta , CD8-Positive T-Lymphocytes , InflammationABSTRACT
Cataloging the diverse cellular architecture of the primate brain is crucial for understanding cognition, behavior, and disease in humans. Here, we generated a brain-wide single-cell multimodal molecular atlas of the rhesus macaque brain. Together, we profiled 2.58 M transcriptomes and 1.59 M epigenomes from single nuclei sampled from 30 regions across the adult brain. Cell composition differed extensively across the brain, revealing cellular signatures of region-specific functions. We also identified 1.19 M candidate regulatory elements, many previously unidentified, allowing us to explore the landscape of cis-regulatory grammar and neurological disease risk in a cell type-specific manner. Altogether, this multi-omic atlas provides an open resource for investigating the evolution of the human brain and identifying novel targets for disease interventions.
Subject(s)
Brain , Multiomics , Animals , Macaca mulatta/genetics , TranscriptomeABSTRACT
Exposure to adversity during early life is linked to lasting detrimental effects on evolutionary fitness across many taxa. However, due to the challenges of collecting longitudinal data, especially in species where one sex disperses, direct evidence from long-lived species remains relatively scarce. Here we test the effects of early life adversity on male and female longevity in a free-ranging population of rhesus macaques (Macaca mulatta) at Cayo Santiago, Puerto Rico. We leveraged six decades of data to quantify the relative importance of ten forms of early life adversity for 6,599 macaques (3,230 male, 3,369 female), with a smaller sample size (N=299) for one form of adversity (maternal social isolation) which required high-resolution behavioral data. We found that individuals who experienced more early life adversity died earlier than those who experienced less adversity. Mortality risk was highest during early life, defined as birth to four years old, suggesting acute survival effects of adversity, but heightened mortality risk was also present in macaques who survived to adulthood. Females and males were affected differently by some forms of adversity, and these differences might be driven by varying energetic demands, female philopatry, and male dispersal. By leveraging data on thousands of macaques collected over decades, our results show that the fitness consequences of early life adversity are not uniform across individuals but vary as a function of the type of adversity, timing, and social context, and thus contribute to our limited but growing understanding of the evolution of early life sensitivities in long-lived species.
ABSTRACT
Monitoring genetic diversity in wild populations is a central goal of ecological and evolutionary genetics and is critical for conservation biology. However, genetic studies of nonmodel organisms generally lack access to species-specific genotyping methods (e.g. array-based genotyping) and must instead use sequencing-based approaches. Although costs are decreasing, high-coverage whole-genome sequencing (WGS), which produces the highest confidence genotypes, remains expensive. More economical reduced representation sequencing approaches fail to capture much of the genome, which can hinder downstream inference. Low-coverage WGS combined with imputation using a high-confidence reference panel is a cost-effective alternative, but the accuracy of genotyping using low-coverage WGS and imputation in nonmodel populations is still largely uncharacterized. Here, we empirically tested the accuracy of low-coverage sequencing (0.1-10×) and imputation in two natural populations, one with a large (n = 741) reference panel, rhesus macaques (Macaca mulatta), and one with a smaller (n = 68) reference panel, gelada monkeys (Theropithecus gelada). Using samples sequenced to coverage as low as 0.5×, we could impute genotypes at >95% of the sites in the reference panel with high accuracy (median r2 ≥ 0.92). We show that low-coverage imputed genotypes can reliably calculate genetic relatedness and population structure. Based on these data, we also provide best practices and recommendations for researchers who wish to deploy this approach in other populations, with all code available on GitHub (https://github.com/mwatowich/LoCSI-for-non-model-species). Our results endorse accurate and effective genotype imputation from low-coverage sequencing, enabling the cost-effective generation of population-scale genetic datasets necessary for tackling many pressing challenges of wildlife conservation.
ABSTRACT
Purpose: Rhesus macaques (Macaca mulatta) are the premier nonhuman primate model for studying human health and disease. We investigated if age was associated with clinically relevant ocular features in a large cohort of free-ranging rhesus macaques from Cayo Santiago, Puerto Rico. Methods: We evaluated 120 rhesus macaques (73 males, 47 females) from 0 to 29 years old (mean ± SD: 12.6 ± 6.4) from September to December 2021. The ophthalmic evaluation included intraocular pressure (IOP) assessment, corneal pachymetry, biomicroscopy, A-scan biometry, automated refraction, and fundus photography after pupil dilation. The associations of age with the outcomes were investigated through multilevel mixed-effects models adjusted for sex and weight. Results: On average, IOP, pachymetry, axial length, and automated refraction spherical equivalent were 18.37 ± 4.68 mmHg, 474.43 ± 32.21 µm, 19.49 ± 1.24 mm, and 0.30 ± 1.70 diopters (D), respectively. Age was significantly associated with pachymetry (ß coefficient = -1.20; 95% confidence interval [CI], -2.27 to -0.14; P = 0.026), axial length (ß coefficient = 0.03; 95% CI, 0.01 to 0.05; P = 0.002), and spherical equivalent (ß coefficient = -0.12; 95% CI, -0.22 to -0.02; P = 0.015). No association was detected between age and IOP. The prevalence of cataracts in either eye was 10.83% (95% CI, 6.34-17.89) and was significantly associated with age (odds ratio [OR] = 1.20; 95% CI, 1.06-1.36; P = 0.004). Retinal drusen in either eye was observed in 15.00% (95% CI, 9.60-22.68) of animals, which was also significantly associated with age (OR = 1.14; 95% CI, 1.02-1.27; P = 0.020). Conclusions: Rhesus macaques exhibit age-related ocular associations similar to those observed in human aging, including decreased corneal thickness, increased axial length, myopic shift, and higher prevalence of cataract and retinal drusen.
Subject(s)
Cataract , Retinal Drusen , Male , Animals , Female , Humans , Infant, Newborn , Infant , Child, Preschool , Child , Adolescent , Young Adult , Adult , Macaca mulatta , Eye , Intraocular Pressure , Tonometry, OcularABSTRACT
The four dengue virus serotypes co-circulate globally and cause significant human disease. Dengue vaccine development is challenging because some virus-specific antibodies are protective, while others are implicated in enhanced viral replication and more severe disease. Current dengue tetravalent vaccines contain four live attenuated serotypes formulated to theoretically induce balanced protective immunity. Among the number of vaccine candidates in clinical trials, only Dengvaxia is licensed for use in DENV seropositive individuals. To simplify live-virus vaccine design, we identify co-evolutionary constraints inherent in flavivirus virion assembly and design chimeric viruses to replace domain II (EDII) of the DENV2 envelope (E) glycoprotein with EDII from DENV4. The chimeric DENV2/4EDII virus replicates efficiently in vitro and in vivo. In male macaques, a single inoculation of DENV2/4EDII induces type-specific neutralizing antibodies to both DENV2 and DENV4, thereby providing a strategy to simplify DENV vaccine design by utilizing a single bivalent E glycoprotein immunogen for two DENV serotypes.
Subject(s)
Dengue Virus , Dengue , Male , Humans , Dengue Virus/genetics , Antibodies, Viral , Serogroup , Viral Envelope Proteins/genetics , Antibodies, NeutralizingABSTRACT
Aging is accompanied by a host of social and biological changes that correlate with behavior, cognitive health and susceptibility to neurodegenerative disease. To understand trajectories of brain aging in a primate, we generated a multiregion bulk (N = 527 samples) and single-nucleus (N = 24 samples) brain transcriptional dataset encompassing 15 brain regions and both sexes in a unique population of free-ranging, behaviorally phenotyped rhesus macaques. We demonstrate that age-related changes in the level and variance of gene expression occur in genes associated with neural functions and neurological diseases, including Alzheimer's disease. Further, we show that higher social status in females is associated with younger relative transcriptional ages, providing a link between the social environment and aging in the brain. Our findings lend insight into biological mechanisms underlying brain aging in a nonhuman primate model of human behavior, cognition and health.
Subject(s)
Neurodegenerative Diseases , Female , Male , Humans , Animals , Macaca mulatta , Transcriptome , Aging/genetics , Social Environment , Solitary NucleusABSTRACT
The link between CD4+ T and B cells during immune responses to DENV and ZIKV and their roles in cross-protection during heterologous infection is an active area of research. Here we used CD4+ lymphocyte depletions to dissect the impact of cellular immunity on humoral responses during a tertiary flavivirus infection in macaques. We show that CD4+ depletion in DENV/ZIKV-primed animals followed by DENV resulted in dysregulated adaptive immune responses. We show a delay in DENV-specific IgM/IgG antibody titers and binding and neutralization in the DENV/ZIKV-primed CD4-depleted animals but not in ZIKV/DENV-primed CD4-depleted animals. This study confirms the critical role of CD4+ cells in priming an early effective humoral response during sequential flavivirus infections. Our work here suggests that the order of flavivirus exposure affects the outcome of a tertiary infection. Our findings have implications for understanding the complex flavivirus immune responses and for the development of effective flavivirus vaccines.
ABSTRACT
A defining feature of catarrhine primates is uniform trichromacy-the ability to distinguish red (long; L), green (medium; M), and blue (short; S) wavelengths of light. Although the tuning of photoreceptors is conserved, the ratio of L:M cones in the retina is variable within and between species, with human cone ratios differing from other catarrhines. Yet, the sources and structure of variation in cone ratios are poorly understood, precluding a broader understanding of color vision variability. Here, we report a large-scale study of a pedigreed population of rhesus macaques (Macaca mulatta). We collected foveal RNA and analyzed opsin gene expression using cDNA and estimated additive genetic variance of cone ratios. The average L:M ratio and standard error was 1.03:1 ± 0.02. There was no age effect, and genetic contribution to variation was negligible. We found marginal sex effects with females having larger ratios than males. S cone ratios (0.143:1 ± 0.002) had significant genetic variance with a heritability estimate of 43% but did not differ between sexes or age groups. Our results contextualize the derived human condition of L-cone dominance and provide new information about the heritability of cone ratios and variation in primate color vision.
Subject(s)
Color Vision , Retinal Cone Photoreceptor Cells , Animals , Color Vision/genetics , Female , Humans , Macaca mulatta/genetics , Male , Opsins , RetinaABSTRACT
Reproduction and survival in most primate species reflects management of both competitive and cooperative relationships. Here, we investigated the links between neuroanatomy and sociality in free-ranging rhesus macaques. In adults, the number of social partners predicted the volume of the mid-superior temporal sulcus and ventral-dysgranular insula, implicated in social decision-making and empathy, respectively. We found no link between brain structure and other key social variables such as social status or indirect connectedness in adults, nor between maternal social networks or status and dependent infant brain structure. Our findings demonstrate that the size of specific brain structures varies with the number of direct affiliative social connections and suggest that this relationship may arise during development. These results reinforce proposed links between social network size, biological success, and the expansion of specific brain circuits.
Subject(s)
Brain , Social Behavior , Animals , Brain/diagnostic imaging , Humans , Macaca mulatta , Temporal LobeABSTRACT
Weather-related disasters are increasing in frequency and severity, leaving survivors to cope with ensuing mental, financial, and physical hardships. This adversity can exacerbate existing morbidities, trigger new ones, and increase the risk of mortality-features that are also characteristic of advanced age-inviting the hypothesis that extreme weather events may accelerate aging. To test this idea, we examined the impact of Hurricane Maria and its aftermath on immune cell gene expression in large, age-matched, cross-sectional samples from free-ranging rhesus macaques (Macaca mulatta) living on an isolated island. A cross section of macaques was sampled 1 to 4 y before (n = 435) and 1 y after (n = 108) the hurricane. Hurricane Maria was significantly associated with differential expression of 4% of immune-cell-expressed genes, and these effects were correlated with age-associated alterations in gene expression. We further found that individuals exposed to the hurricane had a gene expression profile that was, on average, 1.96 y older than individuals that were not-roughly equivalent to an increase in 7 to 8 y of a human life. Living through an intense hurricane and its aftermath was associated with expression of key immune genes, dysregulated proteostasis networks, and greater expression of inflammatory immune cell-specific marker genes. Together, our findings illuminate potential mechanisms through which the adversity unleashed by extreme weather and potentially other natural disasters might become biologically embedded, accelerate age-related molecular immune phenotypes, and ultimately contribute to earlier onset of disease and death.
Subject(s)
Aging/immunology , Macaca/immunology , Survivors/psychology , Age Factors , Animals , Cross-Sectional Studies , Cyclonic Storms , Disasters , Natural Disasters/mortality , Risk FactorsABSTRACT
Social integration and social status can substantially affect an individual's health and survival. One route through which this occurs is by altering immune function, which can be highly sensitive to changes in the social environment. However, we currently have limited understanding of how sociality influences markers of immunity in naturalistic populations where social dynamics can be fully realized. To address this gap, we asked if social integration and social status in free-ranging rhesus macaques (Macaca mulatta) predict anatomical and physiological markers of immunity. We used data on agonistic interactions to determine social status, and social network analysis of grooming interactions to generate measures of individual variation in social integration. As measures of immunity, we included the size of two of the major organs involved in the immune response, the spleen and liver, and counts of three types of blood cells (red blood cells, platelets, and white blood cells). Controlling for body mass and age, we found that neither social status nor social integration predicted the size of anatomical markers of immunity. However, individuals that were more socially connected, i.e., with more grooming partners, had lower numbers of white blood cells than their socially isolated counterparts, indicating lower levels of inflammation with increasing levels of integration. These results build upon and extend our knowledge of the relationship between sociality and the immune system in humans and captive animals to free-ranging primates, demonstrating generalizability of the beneficial role of social integration on health.
Subject(s)
Social Behavior , Social Environment , Animals , Grooming , Macaca mulattaABSTRACT
OBJECTIVE: Milk is the first and continued source of ingested Vitamin D. Extensive studies have been carried out in humans measuring Vitamin D in lactating mothers but to date few values have been obtained for milk of non-human primates and none for rhesus monkeys. Consequently. we have determined Vitamin D and antirachitic activity (ARA) in milk samples obtained from 21 rhesus monkeys. METHODS: Lactating dams were sampled by hand-stripping. 25(OH)D2, Vitamin D2, 25(OH)D3, Vitamin D3 and ARA were assessed in foremilk using LC-MS/MS techniques. RESULTS: 25(OH)D2 and Vitamin D2 were below detectible limits (<0.5 ng/g), 25(OH) D3 =4.2 ± 1.8 ng/ml, Vitamin D3 = 6.1 ± 3.1 ng/ml and ARA = 1080 ± 480 IU/L. CONCLUSION: This is the first report of content of Vitamin D and ARA activity in foremilk of the rhesus monkey and can serve as a reference for future studies.
Subject(s)
Lactation/metabolism , Macaca mulatta , Milk/chemistry , Vitamin D/metabolism , Animals , Calcifediol , Cholecalciferol/metabolism , Chromatography, Liquid , Female , Tandem Mass Spectrometry , Vitamin D/analogs & derivatives , Vitamin D/bloodABSTRACT
BACKGROUND: An individual's microbiome changes over the course of its lifetime, especially during infancy, and again in old age. Confounding factors such as diet and healthcare make it difficult to disentangle the interactions between age, health, and microbial changes in humans. Animal models present an excellent opportunity to study age- and sex-linked variation in the microbiome, but captivity is known to influence animal microbial abundance and composition, while studies of free-ranging animals are typically limited to studies of the fecal microbiome using samples collected non-invasively. Here, we analyze a large dataset of oral, rectal, and genital swabs collected from 105 free-ranging rhesus macaques (Macaca mulatta, aged 1 month-26 years), comprising one entire social group, from the island of Cayo Santiago, Puerto Rico. We sequenced 16S V4 rRNA amplicons for all samples. RESULTS: Infant gut microbial communities had significantly higher relative abundances of Bifidobacterium and Bacteroides and lower abundances of Ruminococcus, Fibrobacter, and Treponema compared to older age groups, consistent with a diet high in milk rather than solid foods. The genital microbiome varied widely between males and females in beta-diversity, taxonomic composition, and predicted functional profiles. Interestingly, only penile, but not vaginal, microbiomes exhibited distinct age-related changes in microbial beta-diversity, taxonomic composition, and predicted functions. Oral microbiome composition was associated with age, and was most distinctive between infants and other age classes. CONCLUSIONS: Across all three body regions, with notable exceptions in the penile microbiome, while infants were distinctly different from other age groups, microbiomes of adults were relatively invariant, even in advanced age. While vaginal microbiomes were exceptionally stable, penile microbiomes were quite variable, especially at the onset of reproductive age. Relative invariance among adults, including elderly individuals, is contrary to findings in humans and mice. We discuss potential explanations for this observation, including that age-related microbiome variation seen in humans may be related to changes in diet and lifestyle. Video abstract.
Subject(s)
Gastrointestinal Microbiome , Microbiota , Animals , Female , Gastrointestinal Microbiome/genetics , Macaca mulatta , Mice , Microbiota/genetics , Puerto Rico , RNA, Ribosomal, 16S/geneticsABSTRACT
Research in the basic biology of ageing is increasingly identifying mechanisms and modifiers of ageing in short-lived organisms such as worms and mice. The ultimate goal of such work is to improve human health, particularly in the growing segment of the population surviving into old age. Thus far, few interventions have robustly transcended species boundaries in the laboratory, suggesting that changes in approach are needed to avoid costly failures in translational human research. In this review, we discuss both well-established and alternative model organisms for ageing research and outline how research in nonhuman primates is sorely needed, first, to translate findings from short-lived organisms to humans, and second, to understand key aspects of ageing that are unique to primate biology. We focus on rhesus macaques as a particularly promising model organism for ageing research owing to their social and physiological similarity to humans as well as the existence of key resources that have been developed for this species. As a case study, we compare gene regulatory signatures of ageing in the peripheral immune system between humans and rhesus macaques from a free-ranging study population in Cayo Santiago. We show that both mRNA expression and DNA methylation signatures of immune ageing are broadly shared between macaques and humans, indicating strong conservation of the trajectory of ageing in the immune system. We conclude with a review of key issues in the biology of ageing for which macaques and other nonhuman primates may uniquely contribute valuable insights, including the effects of social gradients on health and ageing. We anticipate that continuing research in rhesus macaques and other nonhuman primates will play a critical role in conjunction with the model organism and human biodemographic research in ultimately improving translational outcomes and extending health and longevity in our ageing population. This article is part of the theme issue 'Evolution of the primate ageing process'.
Subject(s)
Aging , Gene Regulatory Networks/immunology , Immune System/metabolism , Macaca mulatta/physiology , Models, Animal , Animals , HumansABSTRACT
Little is known about the contribution of virus-specific and cross-reacting antibodies (Abs) or the cellular immune response generated by a primary dengue (DENV) infection on the course of a secondary zika (ZIKV) infection in vivo. Here we show that the length of time between DENV/ZIKV infections has a qualitative impact on controlling early ZIKV replication. Depletion of DENV2-specific Abs in sera confirmed that those type-specific Abs do not contribute to ZIKV control. We show that the magnitude and durability of the neutralizing antibodies (nAbs) induced by a secondary ZIKV infection is modest compared to the response induced after a secondary heterologous DENV infection. Our in vivo results are showing a complex interplay between the cellular and innate immune responses characterized by a high frequency of plasmacytoid dendritic cells (pDC) correlating with an increase in the frequency of DENV antigen specific T cells and a significant control of ZIKV replication which is time dependent. Taken together, our results suggest that early after ZIKV infection other mechanisms such as the innate and cellular immune responses may play a predominant role in controlling ZIKV replication. Regardless of the time elapsed between infections there was no evidence of in vivo antibody-dependent enhancement (ADE) of ZIKV by DENV immunity. These findings have pivotal implications while interpreting ZIKV pathogenesis in flavivirus-experimented populations, diagnostic results interpretation and vaccine designs and schedules among others.