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Comparison of Old World and New World monkeys.
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... Apart from the study by Tronche et al. 28 in mice, to our knowledge, there are currently virtually no studies on episodic-like memory in aged animals. As non-human primates experience aging processes similar to humans 29 www.nature.com/scientificreports/ we expect their episodic-like memory (ELM) to be affected by aging. ...
Episodic memory decline is an early marker of cognitive aging in human. Although controversial in animals and called “episodic-like memory”, several models have been successfully developed, however they rarely focused on ageing. While marmoset is an emerging primate model in aging science, episodic-like memory has never been tested in this species and importantly in aged marmosets. Here, we examined if the recall of the what-when and what-where building blocks of episodic-like memory declines in ageing marmosets. We developed a naturalistic approach using spontaneous exploration of real objects by young and old marmosets in the home cage. We implemented a three-trial task with 1 week inter-trial interval. Two different sets of identical objects were presented in sample trials 1 and 2, respectively. For the test trial, two objects from each set were presented in a former position and two in a new one. We quantified the exploratory behaviour and calculated discrimination indices in a cohort of 20 marmosets. Young animals presented a preserved memory for combined what-where, and what-when components of the experiment, which declined with aging. These findings lead one to expect episodic-like memory deficits in aged marmosets.
... All individuals sampled were young adults to middle-aged adults, with all human subject between 22 to 55 y of age and all chimps 18 to 23 y of age. Baboons and macaques were between 7 to14 y of age, which corresponds to 28 to 55 human years, with the exception of two macaques of 3 and 20 y of age (∼12 and ∼80 human years) (48). The responses and differential cell counts of these individuals, however, were in keeping with other macaques. ...
Despite their close genetic relatedness, apes and African and Asian monkeys (AAMs) differ in their susceptibility to severe bacterial and viral infections that are important causes of human disease. Such differences between humans and other primates are thought to be a result, at least in part, of interspecies differences in immune response to infection. However, because of the lack of comparative functional data across species, it remains unclear in what ways the immune systems of humans and other primates differ. Here, we report the whole-genome transcriptomic responses of ape species (human and chimpanzee) and AAMs (rhesus macaque and baboon) to bacterial and viral stimulation. We find stark differences in the responsiveness of these groups, with apes mounting a markedly stronger early transcriptional response to both viral and bacterial stimulation, altering the transcription of ∼40% more genes than AAMs. Additionally, we find that genes involved in the regulation of inflammatory and interferon responses show the most divergent early transcriptional responses across primates and that this divergence is attenuated over time. Finally, we find that relative to AAMs, apes engage a much less specific immune response to different classes of pathogens during the early hours of infection, up-regulating genes typical of anti-viral and anti-bacterial responses regardless of the nature of the stimulus. Overall, these findings suggest apes exhibit increased sensitivity to bacterial and viral immune stimulation, activating a broader array of defense molecules that may be beneficial for early pathogen killing at the potential cost of increased energy expenditure and tissue damage.
... Old-world monkeys, such as cynomolgus (Macaca fascicularis) and rhesus macaques (Macaca mulatta), are important models for human neurological disorders due to their similarities in brain architecture, anatomy, physiology, and behaviour 15,16 . As many neurodegenerative disorders involve impairment of higher cognitive functions, monkeys have the potential to advance our knowledge of these disorders and validate treatments. ...
INTRODUCTION Non-human primates are important translational models of neurodegenerative disease. We characterized how species, sex, age, and site of sampling affected concentrations of key biomarkers of neurodegeneration.METHODS Amyloid-beta (Aβ40, Aβ42), tau (tTau, pTau), and neurofilament light (NFL) in CSF were measured in 82 laboratory-housed naïve cynomolgus and rhesus macaques of both sexes.RESULTS Aβ40, Aβ42, and NFL were significantly higher in rhesus compared with cynomolgus macaques. tTau and NFL were higher in males. pTau was not affected by species or sex. Site of acquisition only affected NFL, with NFL being higher in CSF acquired from lumbar compared with cisterna magna puncture.DISCUSSION Normative values for key neurodegeneration biomarkers were established for laboratory housed cynomolgus and rhesus macaque monkeys. Differences were observed as a function of species, sex and site of CSF acquisition that should be considered when employing primate models.Research In ContextSystematic review: We reviewed reports characterizing CSF biomarkers of neurodegenerative diseases in non-human primates – an increasingly important model of disease - revealing that studies with laboratory housed macaque monkeys were of small sample size, with a paucity of data about how biomarkers varied as a function of species, sex, age, and site of acquisition.Interpretation: To address this gap, we collected CSF from 82 naïve laboratory housed male and female macaques of two species and measured Aβ40, Aβ42, tTau, pTau, and NFL. In addition to providing normative statistics for concentrations of these biomarkers, we revealed various species and sex differences.Future directions: Establishing normative values of biomarkers is an important step to the efficient development of cynomolgus and rhesus macaques as models of neurodegenerative disorders such as Alzheimer’s disease. Reference values reduce the need for large control groups by which to compare with disease model animals.
... While rhesus macaques are attractive as a model of primate aging due to its high DNA sequence homology with humans (around 92%), the average lifespan of this species in captivity is around 27 years (maximal lifespan is 42 years) 1,2 . The long lifespans of rhesus monkeys required decades-long commitment to accomplish the goals of the calorie restriction study [3][4][5][6] . ...
Human DNA methylation data have previously been used to develop highly accurate biomarkers of aging (“epigenetic clocks”). Subsequent studies demonstrate that similar epigenetic clocks can also be developed for mice and many other mammals. Here, we describe epigenetic clocks for common marmosets ( Callithrix jacchus ) based on novel DNA methylation data generated from highly conserved mammalian CpGs that were profiled using a custom Infinium array (HorvathMammalMethylChip40). From these, we developed and present here, two epigenetic clocks for marmosets that are applicable to whole blood samples. We find that the human-marmoset clock for relative age exhibits moderately high age correlations in two other non-human primate species: vervet monkeys and rhesus macaques. In a separate cohort of marmosets, we tested whether intervention with rapamycin, a drug shown to extend lifespan in mice, would alter the epigenetic age of marmosets, as measured by the marmoset epigenetic clocks. These clocks did not detect significant effects of rapamycin on the epigenetic age of marmoset blood. The common marmoset stands out from other mammals in that it is not possible to build accurate estimators of sex based on DNA methylation data: the accuracy of a random forest predictor of sex (66%) was substantially lower than that observed for other mammals (which is close to 100%). Overall, the epigenetic clocks developed here for the common marmoset are expected to be useful for age estimation of wild-born animals and for anti-aging studies in this species.
... For this study, rhesus monkeys were selected as the animal of choice to determine the brain entry rates of DAS and MPH. Aside from PET and PET tracer considerations, rhesus monkeys share 92% genetic homology with humans and their phenotypic similarities extend to almost all aspects of anatomy, physiology, endocrinology, immunology, neurology, behavior, and aging (Mattison and Vaughan 2017). It is likely that the BBB in human and NHP primate to be similar. ...
RationaleDrugs that rapidly increase dopamine levels have an increased risk of abuse. Dasotraline (DAS) is a dopamine and norepinephrine reuptake inhibitor characterized by slow oral absorption with low potential for abuse. However, it remains unclear whether intravenous (i.v.) administration would facilitate the rapid elevation of dopamine levels associated with stimulant drugs.Objective
To assess the kinetics of DAS across the blood-brain barrier and time to onset of dopamine transporters (DAT) inhibition.Methods
We compared the onset of DAT occupancy and the associated elevation of synaptic dopamine levels in rhesus monkey following i.v. administration of DAS or methylphenidate (MPH) using positron emission tomography (PET). Brain entry times were estimated by reductions in [18F]-FE-PE2I binding to DAT in rhesus monkeys. Elevations of synaptic dopamine were estimated by reductions in [11C]-Raclopride binding to D2 receptors.ResultsIntravenous administration of DAS (0.1 and 0.2 mg/kg) resulted in striatal DAT occupancies of 54% and 68%, respectively; i.v. administered MPH (0.1 and 0.5 mg/kg) achieved occupancies of 69% and 88% respectively. Brain entry times of DAS (22 and 15 min, respectively) were longer than for MPH (3 and 2 min). Elevations in synaptic dopamine were similar for both DAS and MPH however the time for half-maximal displacement by MPH (t = 23 min) was 4-fold more rapid than for DAS (t = 88 min).Conclusions
These results demonstrate that the pharmacodynamics effects of DAS on DAT occupancy and synaptic dopamine levels are more gradual in onset than those of MPH even with i.v. administration that is favored by recreational drug abusers.
... Despite these attractive features, the employment of rhesus macaques in such research remains modest. This is due to both the prohibitive cost of maintaining a colony and the relatively long lifespan of these primates (4). These challenges, however, can be effectively addressed if accurate and robust biomarkers of biological age are established. ...
Methylation levels at specific CpG positions in the genome have been used to develop accurate estimators of chronological age in humans, mice, and other species. Although epigenetic clocks are generally species-specific, the principles underpinning them appear to be conserved at least across the mammalian class. This is exemplified by the successful development of epigenetic clocks for mice and several other mammalian species. Here, we describe epigenetic clocks for the rhesus macaque ( Macaca mulatta ), the most widely used nonhuman primate in biological research. Using a custom methylation array (HorvathMammalMethylChip40), we profiled n=281 tissue samples (blood, skin, adipose, kidney, liver, lung, muscle, and cerebral cortex). From these data, we generated five epigenetic clocks for macaques. These clocks differ with regards to applicability to different tissue types (pan-tissue, blood, skin), species (macaque only or both humans and macaques), and measure of age (chronological age versus relative age). Additionally, the age-based human-macaque clock exhibits a high age correlation (R=0.89) with the vervet monkey ( Chlorocebus sabaeus ), another Old World species. Four CpGs within the KLF14 promoter were consistently altered with age in four tissues (adipose, blood, cerebral cortex, skin). It is expected that the macaque clocks will reveal an epigenetic aging rate associated with a host of health conditions and thus lend themselves for identifying and validating anti-aging interventions.
... In addition to etiological PD models, selecting proper animal to carry out the modeling is equally important. Non-human primates are ideal experimental animals to study the etiology and pathogenesis of PD due to their evolutionary proximity, physiological similarity, close aging process, and the equivalent behavioral symptoms and pathological changes as PD patients (7,8). More importantly, our recent study showed that they can develop PD naturally. ...
Whether direct manipulation of Parkinson’s disease (PD) risk genes in monkey brain can elicit Parkinsonian phenotypes remains an unsolved issue. Here, we employed an adeno-associated virus (AAV)-delivered CRISPR/Cas9 system to directly co-edit PINK1 and DJ-1 genes in the substantia nigra (SN) region of four adult monkey brains. After the operation, two of the monkeys exhibited all classic PD symptoms, including bradykinesia, tremor, and postural instability, accompanied by severe nigral dopaminergic neuron loss (over 60%) and α-synuclein pathology. The aged monkeys were more vulnerable to gene editing by showing faster PD progression, higher final total PD scores, and severer pathologic changes compared with their younger counterparts, suggesting both the genetic and aging factors played important roles in PD development. This gene editing system can be used to develop a large quantity of genetically edited PD monkeys over a short period, thus providing a practical transgenic monkey model for future PD studies.
... The rhesus macaque is the most widely studied NHP model of human aging with an average lifespan of 26 years [30], and a maximum reported lifespan of 40 years [50]. In 1987, the NIA's intramural research program initiated a longitudinal study of CR in NHPs and includes some of the oldest rhesus macaques in recorded history, at well over 40 years of age [50][51][52]. Although it remains unclear why some monkeys lived well beyond the reported average lifespan, postmortem tissue from these oldest-old animals may provide valuable insights into very advanced NHP aging. ...
As human lifespan increases and the population ages, diseases of aging such as Alzheimer’s disease (AD) are a major cause for concern. Although calorie restriction (CR) as an intervention has been shown to increase healthspan in many species, few studies have examined the effects of CR on brain aging in primates. Using postmortem tissue from a cohort of extremely aged rhesus monkeys (22–44 years old, average age 31.8 years) from a longitudinal CR study, we measured immunohistochemically labeled amyloid beta plaques in Brodmann areas 32 and 46 of the prefrontal cortex, areas that play key roles in cognitive processing, are sensitive to aging and, in humans, are also susceptible to AD pathogenesis. We also evaluated these areas for cortical neuron loss, which has not been observed in younger cohorts of aged monkeys. We found a significant increase in plaque density with age, but this was unaffected by diet. Moreover, there was no change in neuron density with age or treatment. These data suggest that even in the oldest-old rhesus macaques, amyloid beta plaques do not lead to overt neuron loss. Hence, the rhesus macaque serves as a pragmatic animal model for normative human aging but is not a complete model of the neurodegeneration of AD. This model of aging may instead prove most useful for determining how even the oldest monkeys are protected from AD, and this information may therefore yield valuable information for clinical AD treatments.
... Using a cynomolgus monkey model, Morizane et al. showed that compared with allogeneic grafts, the autologous transplantation of iPSC-derived neural cells is advantageous for minimizing the immune response in the brain [38]. Male cynomolgus monkeys (Macaca fascicularis) show characteristic age-associated physiological changes comparable to those of human males [46][47][48], which makes them an ideal animal model for translational research, such as developing appropriate testosterone supplementation paradigms and evaluating the potential of stem cell transplantation in this context [49,50]. Thus, preclinical assessment of the feasibility, safety and efficacy of autologous SLCs transplantation in NHP models of TD will be an important step in determining the translational potential of this cell therapy. ...
Rationale: Stem Leydig cells (SLCs) transplantation can restore testosterone production in rodent models and is thus a potential solution for treating testosterone deficiency (TD). However, it remains unknown whether these favorable effects will be reproduced in more clinically relevant large-animal models. Therefore, we assessed the feasibility, safety and efficacy of autologous SLCs transplantation in a testosterone-deficient non-human primate (NHP) model. Methods: Cynomolgus monkey SLCs (CM-SLCs) were isolated from testis biopsies of elderly (> 19 years) cynomolgus monkeys by flow cytometry. Autologous CM-SLCs were injected into the testicular interstitium of 7 monkeys. Another 4 monkeys were injected the same way with cynomolgus monkey dermal fibroblasts (CM-DFs) as controls. The animals were then examined for sex hormones, semen, body composition, grip strength, and exercise activity. Results: We first isolated CD271+ CM-SLCs which were confirmed to expand continuously and show potential to differentiate into testosterone-producing Leydig cells (LCs) in vitro. Compared with CM-DFs transplantation, engraftment of autologous CM-SLCs into elderly monkeys could significantly increase the serum testosterone level in a physiological pattern for 8 weeks, without any need for immunosuppression. Importantly, CM-SLCs transplantation recovered spermatogenesis and ameliorated TD-related symptoms, such as those related to body fat mass, lean mass, bone mineral density, strength and exercise capacity. Conclusion: For the first time, our short-term observations demonstrated that autologous SLCs can increase testosterone levels and ameliorate relevant TD symptoms in primate models. A larger cohort with long-term follow-up will be required to assess the translational potential of autologous SLCs for TD therapy.
... Studies in the more closely genetically related NHP models that can be successfully treated with ART and develop SIV-related comorbidities [146] are also valuable to decipher pathways responsible for accentuated aging and end-organ disease. While studies on NHPs have translational potential for disease-related research [147], studies on aging with HIV/SIV have been limited to comparing infections of young and old animals [148,149]. Epigenetic and other aging biomarkers described above can be incorporated into these studies to fill gaps in our scientific knowledge about biological aging and perhaps identify new approaches to improve healthy aging in PWH. ...
People with HIV (PWH) experience accentuated biological aging, as defined
by markers of inflammation, immune dysfunction, and the epigenetic clock.
They also have an elevated risk of multiple age-associated comorbidities.
To discuss current knowledge, research gaps, and priorities in aging and
age-related comorbidities in treated HIV infection, the NIH program staff
organized a workshop held in Bethesda, Maryland in September 2019. This
review article describes highlights of discussions led by the
Pathogenesis/Basic Science Research working group that focused on three
high priority topics: immunopathogenesis; the microbiome/virome; and aging
and senescence. We summarize knowledge in these fields and describe key
questions for research on the pathogenesis of aging and age-related
comorbidities in PWH. Understanding the drivers and mechanisms underlying
accentuated biological aging is a high priority that will help identify
potential therapeutic targets to improve healthspan in older PWH.
