Rhesus macaques as a tractable physiological model of human ageing

Abstract

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’.

Insights from evolutionarily relevant models for human ageing

“…For example, physiological dysregulation does not appear to vary systematically between men and women, a finding confirmed here in a small-scale horticultural population [88]. As in human studies, rates of DNA methylation showed minimal sex differences in chimpanzees and rhesus macaques [64,89].…”

“…For example, despite considerable diversity in lifespan, primates exhibit broad similarities in the patterning of mortality that distinguish them from other species [55,56]. Primates share physiological similarities with humans that make them highly relevant models for reproductive ageing, metabolic diseases, musculoskeletal ageing, immune function, cardiovascular disease and cognitive decline [57][58][59][60][61][62][63][64]. Finally, given the overall similarities, the variation among primates is specifically informative.…”

“…Several papers in this volume directly apply emergent process approaches: one examines physiological dysregulation in Amazonian horticulturalists using a large biomarker dataset ( [88]), while two others compare age-related changes in gene expression and epigenetic measures of gene-regulation between humans and non-human primates [64,89]. Two other papers translate clinical approaches to frailty to field conditions, examining ecologically relevant measures of physical performance in wild chimpanzees [90] and African foragers and pastoralists [91].…”

“…The contributions in this volume highlight extensive similarities in the ageing processes between humans and other primates across a variety of domains. For example, several contributions demonstrate shared patterns of immunosenescence, both in its specific regulatory mechanisms [64] and its effects on infectious disease burden in the wild [92,93]). While the process of immunosenescence in human ageing is well recognized, the role of infectious disease in driving late-age mortality has diminished in industrialized nations relative to the role of degenerative diseases.…”

“…Collectively, studies in this volume support the hypothesis that the evolution of the extended human lifespan was accompanied by slowing of ageing processes rather than by fundamental changes to these processes. For example, contributions to this volume demonstrate close similarities in age-related DNA methylation between rhesus macaques, chimpanzees and humans, though accelerated and scaled to the expected lifespan of the shorter-lived species [64,89]. Similarly, Kraft et al [88] demonstrate that even in challenging environments, physiological dysregulation in humans proceeds at a slower pace compared with non-human primates.…”