Experiments in macaque monkeys provide critical insights into age-associated changes in cognitive and sensory function

Gray, Daniel T.; Barnes, Carol A.

doi:10.1073/pnas.1902279116

Cited by 52 publications

(39 citation statements)

References 106 publications

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“…In the brain, ageing rhesus macaques undergo a number of structural changes, such as an increase in microglia density [34] and a loss of synapses and dendritic spines in some cortical areas [35], which may be related to observed impairments in behavioural, sensory and cognitive functions [35,36]. Transcriptomic and proteomic studies are increasingly identifying age-associated gene and protein expression changes in a variety of brain regions [37–39].…”

Section: A Rhesus Macaque Model Of Health and Ageingmentioning

confidence: 99%

Rhesus macaques as a tractable physiological model of human ageing

Chiou

Montague

Goldman

et al. 2020

Phil. Trans. R. Soc. B

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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’.

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Section: A Rhesus Macaque Model Of Health and Ageingmentioning

confidence: 99%

Rhesus macaques as a tractable physiological model of human ageing

Chiou

Montague

Goldman

et al. 2020

Phil. Trans. R. Soc. B

View full text Add to dashboard Cite

show abstract

“…In the brain, ageing rhesus macaques undergo a number of structural changes, such as an increase in microglia density [34] and a loss of synapses and dendritic spines in some cortical areas [35], which may be related to observed impairments in behavioural, sensory, and cognitive functions [35,36]. Transcriptomic and proteomic studies are increasingly identifying age-associated gene and protein expression changes in a variety of brain regions [37][38][39].…”

Section: Models For Human Health and Ageingmentioning

confidence: 99%

Rhesus macaques as a tractable physiological model of human ageing

Chiou

Montague

Goldman

et al. 2020

Preprint

View full text Add to dashboard Cite

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 shorter-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 due 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 model organism and human biodemographic research in ultimately improving translational outcomes and extending health and longevity in our ageing population.

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“…Elevated excitability in the hippocampus contributes to impaired memory function in aging (Gray and Barnes, 2019;Haberman et al, 2017a;Samson and Barnes, 2013;. Specifically, heightened activation localized to the DG/CA3 regions of the hippocampus is correlated with memory deficits in aging and in prodromal Alzheimer's disease (AD) such as in patients with amnestic mild cognitive impairment (aMCI) (Bakker et al, 2015(Bakker et al, , 2012Reagh et al, 2018;Yassa et al, , 2010.…”

Section: Introductionmentioning

confidence: 99%

Heterogeneity of age-related neural hyperactivity along the CA3 transverse axis

Lee

Wang

Zeger

et al. 2020

Preprint

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Age-related memory deficits are correlated with neural hyperactivity in the CA1 and CA3 regions of the hippocampus. Abnormal CA3 hyperactivity in aged rats has been proposed to contribute to an imbalance between the normal tradeoff between pattern separation and pattern completion, resulting in overly rigid representations. Recent evidence of functional heterogeneity along the CA3 transverse axis suggests that proximal CA3 supports pattern separation while distal CA3 supports pattern completion. It is not known whether age-related CA3 hyperactivity is uniformly represented along the CA3 transverse axis. We examined the firing rates of CA3 neurons from male young and aged Long-Evans rats along the CA3 transverse axis. Consistent with prior studies, young CA3 cells showed an increasing gradient in mean firing rate from proximal to distal CA3. However, aged CA3 cells showed an opposite trend, with a decreasing gradient from proximal to distal CA3. Thus, CA3 cells in aged rats were hyperactive in proximal CA3, but possibly hypoactive in distal CA3, compared to young rats. We suggest that, in combination with altered inputs from the entorhinal cortex and dentate gyrus, the proximal CA3 region of aged rats may switch from its normal function that reflects the pattern separation output of the DG and instead performs a computation that reflects an abnormal bias toward pattern completion. In parallel, distal CA3 of aged rats may create weaker attractor basins that promote bistable representations under certain conditions.

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Experiments in macaque monkeys provide critical insights into age-associated changes in cognitive and sensory function

Cited by 52 publications

References 106 publications

Rhesus macaques as a tractable physiological model of human ageing

Rhesus macaques as a tractable physiological model of human ageing

Rhesus macaques as a tractable physiological model of human ageing

Heterogeneity of age-related neural hyperactivity along the CA3 transverse axis

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