Immune cell composition varies by age, sex and exposure to social adversity in free-ranging Rhesus Macaques.

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.

The biology of aging in a social world: Insights from free-ranging rhesus macaques.

Social adversity can increase the age-associated risk of disease and death, yet the biological mechanisms that link social adversities to aging remain poorly understood. Long-term naturalistic studies of nonhuman animals are crucial for integrating observations of social behavior throughout an individual's life with detailed anatomical, physiological, and molecular measurements. Here, we synthesize the body of research from one such naturalistic study system, Cayo Santiago, which is home to the world's longest continuously monitored free-ranging population of rhesus macaques (Macaca mulatta). We review recent studies of age-related variation in morphology, gene regulation, microbiome composition, and immune function. We also discuss ecological and social modifiers of age-markers in this population. In particular, we summarize how a major natural disaster, Hurricane Maria, affected rhesus macaque physiology and social structure and highlight the context-dependent and domain-specific nature of aging modifiers. Finally, we conclude by providing directions for future study, on Cayo Santiago and elsewhere, that will further our understanding of aging across different domains and how social adversity modifies aging processes.

Urinary cytokine measurements do not reflect surgery-induced inflammation in rhesus macaques.

Measurement of the health and disease status of free-ranging primates is often limited by a lack of available biomarkers of immune activation and inflammation that can be applied noninvasively via the measurement of urine or fecal samples. Here, we evaluate the potential usefulness of noninvasive urinary measurements of a number of cytokines, chemokines, and other markers of inflammation and infection. We took advantage of surgery-associated inflammation in seven captive rhesus macaques, collecting urine samples before and after the medical interventions. We measured these urine samples for 33 different markers of inflammation and immune activation that are known to be responsive to inflammation and infection in rhesus macaque blood samples, via the Luminex platform. We also measured all samples for concentrations of the soluble urokinase plasminogen activator receptor (suPAR), which we had validated in a prior study as an effective biomarker of inflammation. Despite urine samples being collected in captivity under ideal conditions (clean, no contamination with feces or soil, frozen quickly), 13/33 biomarkers measured via Luminex were found at concentrations below detection limits in >50% of samples. Of the remaining 20 markers, only 2 showed significant increases in response to surgery-IL18 and MPO (myeloperoxidase). However, suPAR measurements of the same samples show a consistent marked increase in response to surgery that is absent from the patterns of IL18 and MPO measurement. Given that our samples were collected under conditions that are greatly preferable to those usually encountered in the field, urinary cytokine measurements via the Luminex platform seem overall unpromising for primate field studies.

The biology of aging in a social world:insights from free-ranging rhesus macaques.

Social adversity can increase the age-associated risk of disease and death, yet the biological mechanisms that link social adversities to aging remain poorly understood. Long-term naturalistic studies of nonhuman animals are crucial for integrating observations of social behavior throughout an individual's life with detailed anatomical, physiological, and molecular measurements. Here, we synthesize the body of research from one such naturalistic study system, Cayo Santiago Island, which is home to the world's longest continuously monitored free-ranging population of rhesus macaques. We review recent studies of age-related variation in morphology, gene regulation, microbiome composition, and immune function. We also discuss ecological and social modifiers of age-markers in this population. In particular, we summarize how a major natural disaster, Hurricane Maria, affected rhesus macaque physiology and social structure and highlight the context-dependent and domain-specific nature of aging modifiers. Finally, we conclude by providing directions for future study, on Cayo Santiago and elsewhere, that will further our understanding of aging across different domains and how social adversity modifies aging processes.

Greater variability in rhesus macaque (Macaca mulatta) endocranial volume among males than females.

The greater male variability (GMV) hypothesis proposes that traits are more variable among males than females, and is supported by numerous empirical studies. Interestingly, GMV is also observed for human brain size and internal brain structure, a pattern which may have implications for sex-biased neurological and psychiatric conditions. A better understanding of neuroanatomical variability in non-human primates may illuminate whether certain species are appropriate models for these conditions. Here, we tested for sex differences in the variability of endocranial volume (ECV, a proxy for brain size) in a sample of 542 rhesus macaques (Macaca mulatta) from a large pedigreed free-ranging population. We also examined the components of phenotypic variance (additive genetic and residual variance) to tease apart the potential drivers of sex differences in variability. Our results suggest that males exhibit more variable ECVs, and that this pattern reflects either balancing/disruptive selection on male behaviour (associated with alternative male mating strategies) or sex chromosome effects (associated with mosaic patterns of X chromosome gene expression in females), rather than extended neurodevelopment among males. This represents evidence of GMV for brain size in a non-human primate species and highlights the potential of rhesus macaques as a model for sex-biased brain-based disorders.

The rhesus macaque as a success story of the Anthropocene.

Of all the non-human primate species studied by researchers, the rhesus macaque (Macaca mulatta) is likely the most widely used across biological disciplines. Rhesus macaques have thrived during the Anthropocene and now have the largest natural range of any non-human primate. They are highly social, exhibit marked genetic diversity, and display remarkable niche flexibility (which allows them to live in a range of habitats and survive on a variety of diets). These characteristics mean that rhesus macaques are well-suited for understanding the links between sociality, health and fitness, and also for investigating intra-specific variation, adaptation and other topics in evolutionary ecology.

Variation and heritability of retinal cone ratios in a free-ranging population of rhesus macaques.

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.

Aging and Senescence across Reproductive Traits and Survival in Superb Fairy-Wrens (Malurus cyaneus).

AbstractWhy do senescence rates of fitness-related traits often vary dramatically? By considering the full aging trajectories of multiple traits, we can better understand how a species' life history shapes the evolution of senescence within a population. Here, we examined age-related changes in sex-specific survival, reproduction, and several components of reproduction using a long-term study of a cooperatively breeding songbird, the superb fairy-wren (Malurus cyaneus). We compared aging patterns between traits by estimating standardized rates of maturation, age of onset of senescence, and rates of senescence while controlling for confounding factors reflecting individual variability in life history. We found striking differences in aging and senescence patterns between survival and reproduction as well as between reproductive traits. In both sexes, survival started to decline from maturity onward. In contrast, all reproductive traits showed improvements into early adulthood, and many showed little or no evidence of senescence. In females, despite senescence in clutch size, number of offspring surviving to independence did not decline in late life, possibly due to improvements in maternal care with age. Superb fairy-wrens have exceptionally high levels of extragroup paternity, and while male within-group reproductive success did not change with age, extragroup reproductive success showed a dramatic increase in early ages, followed by a senescent decline, suggesting that male reproductive aging is driven by sexual selection. We discuss how the superb fairy-wrens' complex life history may contribute to the disparate aging patterns across different traits.

Do the ages of parents or helpers affect offspring fitness in a cooperatively breeding bird?

Age-related changes in parental phenotypes or genotypes can impact offspring fitness, but separating germline from nongermline transgenerational effects of ageing is difficult for wild populations. Further, in cooperatively breeding species, in addition to parental ages, the age of 'helpers' attending offspring may also affect juvenile performance. Using a 30-year study of a cooperative breeder with very high rates of extra-pair paternity, the superb fairy-wren (Malurus cyaneus), we investigated the effects of maternal, paternal and helper ages on three measures of offspring performance: nestling weight, juvenile survival to independence and recruitment to the breeding population. Mothers with a longer lifespan had offspring with higher juvenile survival, indicating selective disappearance, but the effect of maternal age on juvenile survival was of similar magnitude but negative. For extra-pair offspring, there was no evidence of any effect of the ages of either the genetic sire or the cuckolded 'social' father. However, for within-pair offspring, there was a positive effect of paternal age on juvenile survival, which we suggest may be driven by sexual selection. There were positive associations between the average age of helpers attending a nest and two of the three aspects of offspring performance; these effects were stronger than any of the effects of parental age. In general, the multiple associations between offspring fitness and the ages of adults around them appeared to be driven more by age-related changes in environmental effects than by age-related changes in the germline.

Digest: Indirect genetic effects of males on female reproductive traits in the wild.

The indirect genetic effects of fathers on the expression and evolution of female reproductive traits in the wild is not well understood. In a wild population of great tits (Parus major), Evans et al. estimated the genetic and nongenetic effects of male mates on two female reproductive traits, lay date and clutch size. The estimated heritability of lay date (but not of clutch size) was increased by 1.5 times after accounting for male indirect genetic effects. This finding illustrates the importance of considering the effects of social partners in classic quantitative genetic models.

Ageing with a silver-spoon: A meta-analysis of the effect of developmental environment on senescence.

What determines variation between individuals in how they senesce, and are environmental conditions experienced during development relevant to late-life performance? We report a meta-analysis of studies of wild populations to determine how the quality of the environment experienced during development affects rates of survival and reproductive senescence. From studies of 14 bird or mammal species, we calculated effect sizes for the interaction between the effects of environmental quality during development and age in predicting survival (N = 18) or reproduction (N = 30) over time in late life. We found no evidence that developmental environment affected rates of survival senescence (ßmean = -1.2 × 10-4 ± 0.022SE). However, a better developmental environment was associated with slower rates of reproductive senescence in late life (ßmean = 0.062 ± 0.023SE), indicating a small, but significant, "silver-spoon" effect of early-life conditions that persisted through to late life. Our results illustrate how the effects of environmental conditions during development can persist throughout life, and indicate one possible cause of phenotypic plasticity in senescence.

Retrospective Observational Review of Percutaneous Cannulation for Extracorporeal Membrane Oxygenation.

Cannulation is a potentially complex event in the conduct of venovenous extracorporeal membrane oxygenation (VV-ECMO) for patients with severe respiratory failure. The purpose of this article is to describe our approach to cannulation and its complications. A single-center, retrospective, observational cohort, electronic note review study of patients commenced on VV-ECMO for severe respiratory failure. We identified 348 cannulae placed in 179 patients commenced on VV-ECMO from December 2011 to March 2015. All cannulations were successful. There were no deaths related to cannulation, and complications included one arterial injury, one cardiac tamponade, two cases of venous insufficiency, and five cannula site infections. Percutaneous cannulation for VV-ECMO can be achieved with a high degree of success and low complication rate by intensivists using ultrasound and fluoroscopic guidance.

Prevalence of Venous Thrombosis Following Venovenous Extracorporeal Membrane Oxygenation in Patients With Severe Respiratory Failure.

OBJECTIVES: Venovenous extracorporeal membrane oxygenation for patients with severe respiratory failure is increasingly common. There has been a significant change in the population, technology, and approach used for venovenous extracorporeal membrane oxygenation over the last 10 years. The objective of this study is to describe the prevalence of postdecannulation deep vein thrombosis in the cannulated vessel in adults who have received venovenous extracorporeal membrane oxygenation for severe respiratory failure. DESIGN: A single-center, retrospective, observational cohort, electronic note review study. SETTING: Tertiary referral university teaching hospital. PATIENTS: Patients commenced on venovenous extracorporeal membrane oxygenation for severe respiratory failure. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We identified 103 patients commenced on extracorporeal membrane oxygenation with 81 survivors from December 2011 to February 2014. We performed postdecannulation venous Doppler ultrasound in 88.9% of extracorporeal membrane oxygenation survivors. The prevalence of deep vein thrombosis in the cannulated vessel following extracorporeal membrane oxygenation is 8.1/1,000 cannula days in patients who were screened. CONCLUSIONS: The prevalence of deep vein thrombosis following decannulation from extracorporeal membrane oxygenation for severe respiratory failure is clinically significant, and routine venous Doppler ultrasound following decannulation is warranted in this population.