Aged Macaques Research Articles

Study on the Standardized Preparation of NK Cells and the Mechanism of Anti-aging of Rhesus Monkey PBMC

Background: Natural killer (NK) cells are an important part of the immune system and play a central role in cell-mediated immune responses. Recent studies have shown that NK cells promote organ rejuvenation, thus achieving anti-aging effects from the inside to out. Methods: We amplified and cultured human peripheral blood NK cells and the positive rate reached 43.91%. After purification, the positive rate reached 92.65%. The cultured NK showed a good killing effect on tumor cells and the NK cells reached the standard preparation scale. The NK cells cultured by us were co-cultured with the PBMC of aging macaques and the quantitative PCR and WB results showed that the expression of aging gene and aging protein of the PBMC of aging macaques decreased significantly after co-culture, with statistical significance (P less than 0.01). Result: These results indicate that NK cells prepared with standard preparation have anti-aging effect, which will have extensive significance in preclinical research.

Investigation on thyroid gene network of aged macaques subjected to bone marrow mesenchymal stem cells treatment: Revealed from genic transcriptome analysis

Investigation on thyroid gene network of aged macaques subjected to bone marrow mesenchymal stem cells treatment: Revealed from genic transcriptome analysis

Deficiency of SECTM1 impairs corneal wound healing in aging.

The corneal epithelium is the outermost transparent barrier of the eyeball and undergoes continuous self-renewal by limbal stem cells (LSCs) during its lifetime; however, the impact of aging on LSCs remains largely unknown. Here, we showed that the healing ability of the cornea in elderly macaques (Macaca fascicularis) was significantly decreased compared to that of younger macaques. This delayed wound closure accompanied a disordered cell arrangement and corneal opacity. A novel cytokine, Secreted and Transmembrane 1 (SECTM1), was found to facilitate corneal healing and was upregulated in young macaques upon wounding. Mechanistically, SECTM1 is essential for LSC migration and proliferation, and may partially function through Cell Division Cycle Associated 7 (CDCA7). Notably, the topical application of SECTM1 to aged wounded corneas dramatically promoted re-epithelialization and improved corneal transparency in both mice and macaques. Our work suggests that aging may impair the expression of healing response factors and injury repair in non-human primate corneas, and that SECTM1 application could potentially benefit corneal wound healing in clinical treatment.

Kynurenic acid inflammatory signaling expands in primates and impairs prefrontal cortical cognition.

Cognitive deficits from dorsolateral prefrontal cortex (dlPFC) dysfunction are common in neuroinflammatory disorders, including long-COVID, schizophrenia and Alzheimer's disease, and have been correlated with kynurenine inflammatory signaling. Kynurenine is further metabolized to kynurenic acid (KYNA) in brain, where it blocks NMDA and α7-nicotinic receptors (nic-α7Rs). These receptors are essential for neurotransmission in dlPFC, suggesting that KYNA may cause higher cognitive deficits in these disorders. The current study found that KYNA and its synthetic enzyme, KAT II, have greatly expanded expression in primate dlPFC in both glia and neurons. Local application of KYNA onto dlPFC neurons markedly reduced the delay-related firing needed for working memory via actions at NMDA and nic-α7Rs, while inhibition of KAT II enhanced neuronal firing in aged macaques. Systemic administration of agents that reduce KYNA production similarly improved cognitive performance in aged monkeys, suggesting a therapeutic avenue for the treatment of cognitive deficits in neuroinflammatory disorders.

Nanoscale imaging of pT217-tau in aged rhesus macaque entorhinal and dorsolateral prefrontal cortex: Evidence of interneuronal trafficking and early-stage neurodegeneration.

Tau phosphorylated at threonine-217 (pT217-tau) is a novel fluid-based biomarker that predicts onset of Alzheimer's disease (AD) symptoms, but little is known about how pT217-tau arises in the brain, as soluble pT217-tau is dephosphorylated post mortem in humans. We used multilabel immunofluorescence and immunoelectron microscopy to examine the subcellular localization of early-stage pT217-tau in entorhinal and prefrontal cortices of aged macaques with naturally occurring tau pathology and assayed pT217-tau levels in plasma. pT217-tau was aggregated on microtubules within dendrites exhibiting early signs of degeneration, including autophagic vacuoles. It was also seen trafficking between excitatory neurons within synapses on spines, where it was exposed to the extracellular space, and thus accessible to cerebrospinal fluid (CSF)/blood. Plasma pT217-tau levels increased across the age span and thus can serve as a biomarker in macaques. These data help to explain why pT217-tau predicts degeneration in AD and how it gains access to CSF and plasma to serve as a fluid biomarker.

Physiological characterization of a macaque model of presbycusis

Age-related hearing loss (presbycusis) is the leading cause of hearing loss worldwide, but current human studies do not separate this pathology from lifetime noise exposure. Laboratory macaques live in environments with minimal noise-induced hearing trauma and have long lifespans, making them optimal presbycusis models. We describe age-related auditory changes using two clinical, non-invasive physiological measures in aging macaques: distortion product otoacoustic emissions (DPOAEs) and auditory brainstem responses (ABRs). ABRs and DPOAEs were measured in anesthetized young (6–9 years old, n = 36 ears) and aging (26–35 years old, n = 20 ears) Macaca mulatta. ABR and DPOAE thresholds were elevated in aging subjects compared to young macaques at all tested frequencies. ABR thresholds were significantly correlated with age for frequencies >8 kHz, but DPOAE thresholds were not, a pattern likely attributable to a high-frequency ceiling effect for DPOAE measures. For frequencies <8 kHz, DPOAE thresholds showed significant correlation with age. However, this was not observed with ABR thresholds, suggesting differential sensitivity to age-related changes for auditory nerve and brainstem function compared to cochlear outer hair cell function. Ongoing analysis on temporal processing/adaptation metrics will further elucidate age-related changes. Future work will correlate these findings with histological analysis. [Work Supported by NIH R01-DC-015988.]

SHIV-C109p5 NHP induces rapid disease progression in elderly macaques with extensive GI viral replication.

CCR5-tropic simian/human immunodeficiency viruses (SHIV) with clade C transmitted/founder envelopes represent a critical tool for the investigation of HIV experimental vaccines and microbicides in nonhuman primates, although many such isolates lead to spontaneous viral control post infection. Here, we generated a high-titer stock of pathogenic SHIV-C109p5 by serial passage in two rhesus macaques (RM) and tested its virulence in aged monkeys. The co-receptor usage was confirmed before infecting five geriatric rhesus macaques (four female and one male). Plasma viral loads were monitored by reverse transcriptase-quantitative PCR (RT-qPCR), cytokines by multiplex analysis, and biomarkers of gastrointestinal damage by enzyme-linked immunosorbent assay. Antibodies and cell-mediated responses were also measured. Viral dissemination into tissues was determined by RNAscope. Intravenous SHIV-C109p5 infection of aged RMs leads to high plasma viremia and rapid disease progression; rapid decrease in CD4+ T cells, CD4+CD8+ T cells, and plasmacytoid dendritic cells; and wasting necessitating euthanasia between 3 and 12 weeks post infection. Virus-specific cellular immune responses were detected only in the two monkeys that survived 4 weeks post infection. These were Gag-specific TNFα+CD8+, MIP1β+CD4+, Env-specific IFN-γ+CD4+, and CD107a+ T cell responses. Four out of five monkeys had elevated intestinal fatty acid binding protein levels at the viral peak, while regenerating islet-derived protein 3α showed marked increases at later time points in the three animals surviving the longest, suggesting gut antimicrobial peptide production in response to microbial translocation post infection. Plasma levels of monocyte chemoattractant protein-1, interleukin-15, and interleukin-12/23 were also elevated. Viral replication in gut and secondary lymphoid tissues was extensive.IMPORTANCESimian/human immunodeficiency viruses (SHIV) are important reagents to study prevention of virus acquisition in nonhuman primate models of HIV infection, especially those representing transmitted/founder (T/F) viruses. However, many R5-tropic SHIV have limited fitness in vivo leading to many monkeys spontaneously controlling the virus post acute infection. Here, we report the generation of a pathogenic SHIV clade C T/F stock by in vivo passage leading to sustained viral load set points, a necessity to study pathogenicity. Unexpectedly, administration of this SHIV to elderly rhesus macaques led to extensive viral replication and fast disease progression, despite maintenance of a strict R5 tropism. Such age-dependent rapid disease progression had previously been reported for simian immunodeficiency virus but not for R5-tropic SHIV infections.

Localization of PDE4D, HCN1 channels, and mGluR3 in rhesus macaque entorhinal cortex may confer vulnerability in Alzheimer's disease.

Alzheimer's disease cortical tau pathology initiates in the layer II cell clusters of entorhinal cortex, but it is not known why these specific neurons are so vulnerable. Aging macaques exhibit the same qualitative pattern of tau pathology as humans, including initial pathology in layer II entorhinal cortex clusters, and thus can inform etiological factors driving selective vulnerability. Macaque data have already shown that susceptible neurons in dorsolateral prefrontal cortex express a "signature of flexibility" near glutamate synapses on spines, where cAMP-PKA magnification of calcium signaling opens nearby potassium and hyperpolarization-activated cyclic nucleotide-gated channels to dynamically alter synapse strength. This process is regulated by PDE4A/D, mGluR3, and calbindin, to prevent toxic calcium actions; regulatory actions that are lost with age/inflammation, leading to tau phosphorylation. The current study examined whether a similar "signature of flexibility" expresses in layer II entorhinal cortex, investigating the localization of PDE4D, mGluR3, and HCN1 channels. Results showed a similar pattern to dorsolateral prefrontal cortex, with PDE4D and mGluR3 positioned to regulate internal calcium release near glutamate synapses, and HCN1 channels concentrated on spines. As layer II entorhinal cortex stellate cells do not express calbindin, even when young, they may be particularly vulnerable to magnified calcium actions and ensuing tau pathology.

Chronic GCPII (glutamate-carboxypeptidase-II) inhibition reduces pT217Tau levels in the entorhinal and dorsolateral prefrontal cortices of aged macaques.

Current approaches for treating sporadic Alzheimer's disease (sAD) focus on removal of amyloid beta 1-42 (Aβ1-42) or phosphorylated tau, but additional strategies are needed to reduce neuropathology at earlier stages prior to neuronal damage. Longstanding data show that calcium dysregulation is a key etiological factor in sAD, and the cortical neurons most vulnerable to tau pathology show magnified calcium signaling, for example in dorsolateral prefrontal cortex (dlPFC) and entorhinal cortex (ERC). In primate dlPFC and ERC, type 3 metabotropic glutamate receptors (mGluR3s) are predominately post-synaptic, on spines, where they regulate cAMP-calcium signaling, a process eroded by inflammatory glutamate carboxypeptidase II (GCPII) actions. The current study tested whether enhancing mGluR3 regulation of calcium via chronic inhibition of GCPII would reduce tau hyperphosphorylation in aged macaques with naturally-occurring tau pathology. Aged rhesus macaques were treated daily with the GCPII inhibitor, 2-MPPA (2-3-mercaptopropyl-penanedioic acid (2-MPPA)),Aged rhesus macaques were treated daily with the GCPII inhibitor, 2-MPPA (2-3-mercaptopropyl-penanedioic acid (2-MPPA)). Aged macaques that received 2-MPPA had significantly lower pT217Tau levels in dlPFC and ERC, and had lowered plasma pT217Tau levels from baseline. pT217Tau levels correlated significantly with GCPII activity in dlPFC. Both 2-MPPA- and vehicle-treated monkeys showed cognitive improvement; 2-MPPA had no apparent side effects. Exploratory CSF analyses indicated reduced pS202Tau with 2-MPPA administration, confirmed in dlPFC samples. These data provide proof-of-concept support that GCPII inhibition can reduce tau hyperphosphorylation in the primate cortices most vulnerable in sAD. GCPII inhibition may be particularly helpful in reducing the risk of sAD caused by inflammation. These data in nonhuman primates should encourage future research on this promising mechanism. Inflammation is a key driver of sporadic Alzheimer's disease.GCPII inflammatory signaling in brain decreases mGluR3 regulation of calcium.Chronic inhibition of GCPII inflammatory signaling reduced pT217Tau in aged monkeys.GCPII inhibition is a novel strategy to help prevent tau pathology at early stages.

Gene network analysis of the hypothalamus of rhesus macaques in different ages

Gene network analysis of the hypothalamus of rhesus macaques in different ages

An Advax-CpG55.2™ adjuvanted recombinant spike protein vaccine protects cynomolgus macaques from a homologous SARS-CoV-2 virus challenge

Traditional protein-based vaccine approaches to COVID-19 were overshadowed by the new mRNA and adenoviral vector vaccine approaches which were first to receive marketing authorization. The current study tested for the first time in repurposed aged (median 15.4 years) cynomolgus macaques, a novel Advax-CpG55.2™ adjuvanted recombinant extracellular domain spike protein trimer antigen for immunogenicity, protection and safety. Nine animals received two intramuscular injections 10 days apart of recombinant spike protein (25 μg) with Advax-CpG55.2™ (10 mg/200 μg) and 5 controls received saline injections. Serum antibody levels were followed for 3 months and then the animals were challenged with SARS-CoV-2 virus. Clinical signs, local reactions, body weight, food consumption and antibody levels were monitored till termination on either day 3 or 7 post-infection. Two weeks after the second dose, 8/9 immunized macaques had high serum spike and receptor binding domain binding antibodies that were able to cross-neutralize Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2) and, to a lesser extent, Omicron variants (B.1.1.529 ). Antibody levels decayed over the subsequent 3 months, and minimal neutralizing antibody was detectable immediately prior to the challenge which used a vaccine-homologous Wuhan-like ancestral virus. Of the nine vaccinated animals, only one 18-year-old female sacrificed at d3 had low levels of lung virus, versus 100 % of the control animals. Four of 5 (80 %) control animals had positive lung staining for SARS-CoV-2 virus versus just 1 of 9 (11 %) in the immunized group. The immunized animals exhibited better maintenance of appetite post-challenge. Neutralizing antibody levels rebounded rapidly in immunized animals, post-challenge. This data supports the benefits of Advax-CpG adjuvanted recombinant spike protein vaccine in protecting against a homologous SARS-CoV-2 infection.

Understanding of SARS-CoV-2 pathogenicity in COVID-19 cynomolgus macaque model and consideration of its reinfection

Abstract Although rapid vaccination has been progressing in the world as a countermeasure against COVID-19, the pandemic of SARS-CoV-2 is still raging worldwide due to the continuous emergence of several variants. We have established the COVID-19 cynomolgus macaque (CM) model using healthy young CMs and advanced-age CMs and the differences observed between the pathologies of young and elderly macaques were similar that those seen in humans. In the present study, we analyzed viral dynamics and pathology of SARS-CoV-2 variants of concern (VOCs) from Wuhan to Omicrons using the COVID-19 CM model. Delta infection displayed a greater virulence and Omicron infection showed a lesser virulence. Elucidation of how adaptive immunity in patients is induced by SARS-CoV-2 natural infection is critical for establishing a vaccine strategy, serologic therapies, public health control and prediction of infection. Therefore, we conducted the prolonged rechallenge analysis using the COVID-19 CM model reinoculated with either the same or a different strain of SARS-CoV-2 that was used for the initial infection. Re-infection was confirmed between different virus strains and PCR re-positivity was also observed between same VOC strain in some cases. Anti-RBD antibodies against Wuhan, Alpha, and Delta, were well induced by each VOC infection, but not against Omicrons. Antigen-specific cellular responses are also currently being analyzed. Overall, studies using COVID-19 CM models should contribute to the elucidation of the complicated pathophysiology of COVID-19. In addition, COVID-19 CM model should be useful for understand the virus evolution and to consider vaccine strategy to overcome the COVID-19 pandemic. AMED JP21fk0108414 AMED JP223fa727002 JSPS 21K19395

Neural cell isolation from adult macaques for high-throughput analyses and neurosphere cultures.

The low number of neural progenitor cells (NPCs) present in the adult and aged primate brains represents a challenge for generating high-yield and viable in vitro cultures of primary brain cells. Here we report a step-by-step approach for the fast and reproducible isolation of high-yield and viable primary brain cells, including mature neurons, immature cells and NPCs, from adult and aged macaques. We describe the anesthesia, transcardial perfusion and brain tissue preparation; the subsequent microdissection of the regions of interest and their enzymatic dissociation, leading to the separation of single cells. The cell isolation steps of our protocol can also be used for routine cell culturing, in particular for NPC expansion and differentiation, suitable for studies of hippocampal neurogenesis in the adult macaque brain. The purified primary brain cells are largely free from myelin debris and erythrocytes, paving the way for multiple downstream applications in vitro and in vivo. When combined with single-cell profiling techniques, this approach allows an unbiased and comprehensive mapping of cell states in the adult and aged macaque brain, which is needed to advance our understanding of human cognitive and neurological diseases. The neural cell isolation protocol requires 4 h and a team of four to six users with expertize in primary brain cell isolation to avoid tissue hypoxia during the time-sensitive steps of the procedure.

Bone Marrow Mesenchymal Stem Cells Derived from Juvenile Macaques Reversed the Serum Protein Expression Profile in Aged Macaques.

The aim of the study was to reveal the changes in serum protein composition and content in macaques during the process of ageing, and explore the effect of bone marrow mesenchymal stem cell (BMMSC) on the serum protein expression profile in elderly macaques. Naturally ageing macaques were assessed according to age. BMMSCs were intravenously infused into aged macaques. In addition, peripheral blood was collected to obtain serum for dataindependent acquisition (DIA) protein sequencing to identify aging-related indicators. One hundred eighty days after macaques received BMMSC treatment, haemoxylin and eosin (HE) staining was performed to observe the morphology and structure of aortic arches. Compared to infant and young control macaques, aged macaques showed erythema on the face, dry skin, reduced amounts of hair on the head and back, and paleness. Cultured BMMSCs from the 4th passage (P4 BMMSCs) were grown in accordance with standards used to culture mesenchymal stem cells. After BMMSC treatment, the assessed aortic arches showed no calcium salt deposition or cell necrosis, and the characteristics of the serum protein expression profile tended to be similar to that of the infant and young groups, with the expression of 41 proteins upregulated with age and that of 30 proteins downregulated with age but upregulated after BMMSC treatment. Moreover, we identified 44 significantly differentially expressed proteins between the aged model and treatment groups; 11 of the upregulated proteins were related to vascular ageing, neuronal ageing and haematopoiesis, and 33 of the downregulated proteins were associated with neuronal ageing, cardiovascular disease, and tumours. Interestingly, S100 expression in serum was significantly decreased, COMP expression was significantly increased, NKAP expression reappeared, and LCN2, CSF1R, CORO1C, CSTB and RSU-1 expression disappeared after BMMSC treatment. BMMSCs can reverse ageing-related serum protein expression.

Single-cell transcriptome atlas of spontaneous dry age-related macular degeneration in macaques

Age-related macular degeneration is the leading cause of irreversible visual impairment in the elderly. It manifests in two forms, wet and dry. However, the mechanisms underlying spontaneous dry age-related macular degeneration (SD-AMD) remain unclear. Herein, we constructed a single-cell retinal transcription atlas in aged non-human primates with SD-AMD. Retinal tissues affected by SD-AMD exhibited a more degenerative and dysfunctional transcriptomic landscape, with global activation of the oxidative stress response and apoptotic signaling pathway. We found two distinct Müller glia subtypes in normal aged and SD-AMD macaques, one exhibiting a photoreceptor-like transcriptome and the other exhibiting a typical Müller glia transcriptome. As SD-AMD progressed, the proportion of photoreceptor-like Müller glial cells decreased, and photoreceptor-function-associated genes were downregulated, indicating weaker Müller glia potential to transit into photoreceptor-like functional states. Microglial cells showed activated features, and the complement system was activated during disease pathogenesis. We also found that the disruption of iron homeostasis and ferroptosis could promote SD-AMD pathogenesis in neural cells. Further experimentation revealed that a ferroptosis inhibitor exerted a profound rescuing effect in SD-AMD mouse models. Based on these results, our study introduces a path toward understanding the pathogenesis of SD-AMD in a non-human primate model at single-cell resolution.

M1 muscarinic acetylcholine receptor positive allosteric modulators do not disrupt sleep in aged cynomolgus macaques

AbstractBackgroundAge‐related changes in sleep may directly contribute to cognitive dysfunction and underlying pathological progression contributing to Alzheimer’s Disease or related dementias (AD/ADRDs). While acetylcholinesterase inhibitors (AChEIs) are FDA‐approved for the treatment of AD‐related cognitive impairments, these drugs also disrupt sleep. Positive allosteric modulators (PAMs) targeting the M1 muscarinic acetylcholine receptor (M1 mAChR) have produced cognitive and arousal enhancing as well as sleep‐modifying effects in aged and/or AD rodents models. The present study provided the first comparison of baseline sleep measures in young and old monkeys, then examined the effects of novel M1 mAChR PAMs VU0486846 and VU0453595, compared with the AChEI, Donepezil on sleep in aged monkeys.MethodEight young adult (4 male/4 female, 6‐8 years old) and 10 aged cynomolgus macaques (6 males/4 females, 19‐25 years old) were implanted with subcranial electrodes and a wireless transmitter (L04, DSI) for undisturbed telemetric recording of electroencephalography (EEG) from their home cage. After baseline sleep assessments, aged monkeys were tested once weekly with donepezil (3.0‐10 mg/kg, PO), VU0486846 (3.0‐30 mg/kg, PO), or VU0453595 (1.0‐10 mg/kg, PO), administered 2 hours prior to lights out (0600:1800 light:dark schedule). EEG was recorded and sleep stages including total sleep time (TST), % TST in rapid eye movement sleep (REM), N1, N2, and N3 non‐REM sleep were determined and summed across the 12 hour dark period.ResultAged monkeys showed significantly less % TST in N3 and REM sleep and increased N1 sleep compared to young monkeys. Donepezil dose‐dependently reduced TST, increased % REM and trended toward a decrease in N2 and N3 stage sleep. In contrast, M1 PAMs, within dose ranges known to be physiologically active in monkeys, did not alter sleep parameters.ConclusionAged‐related and donepezil‐mediated sleep disruptions in aged monkeys are consistent with the clinical literature. Lack of effects by M1 mAChR PAMs in aged monkeys when dosed prior to lights out may suggest fewer disruptive effects compared to AChEIs or that there is insufficient cholinergic tone for an M1 PAM to alter sleep. Future studies will assess the arousal enhancing effects of M1 PAMs when dosed during waking periods in aged monkeys.Funding: AG054622, DA017763

Improvement in Accommodation and Dynamic Range of Focus After Laser Scleral Microporation: A Potential Treatment for Presbyopia.

To examine the ocular changes in accommodation, wavefront aberrations, and dynamic range of focus (DROF) after laser scleral microporation (LSM) for treating presbyopia. Four presbyopic aged cynomolgus macaques (>13 years; n = 8 eyes) were included. All eyes received LSM with erbium: yttrium-aluminum-garnet laser. Spherical equivalent, true accommodation, pseudo-accommodation, wavefront aberrations, and extended range of focus (EROF), or collectively known as DROF, were evaluated using a ray tracing aberrometer. True accommodation referred to the difference in spherical equivalent between distance and near vision, whereas EROF (sum of true and pseudo-accommodation) was determined by measuring the difference in diopters (D) between near and distance through-focus curves, at 50% threshold of the visual Strehl ratio of optical transfer function. From before to seven months after surgery, there was a significant increase in true accommodation from 0.6 ± 1.0 D before surgery to 5.9 ± 2.8 D at seven months after surgery (P < 0.001). EROF increased significantly from 3.4 ± 1.0 D before surgery to 11.1 ± 4.6 D at seven months after surgery (P < 0.001). Ocular aberrations did not vary significantly between preoperative and various postoperative timepoints in either disaccommodated or accommodated states (P > 0.05). No adverse event such as scleral perforation or hypotony was noted. This non-human primate study demonstrated that LSM serves as a novel therapy for improving accommodation and DROF function biomechanically, with a positive response observed throughout the seven-month postoperative period. This proof-of-concept study highlights the potential of LSM as a novel treatment for vision recovery in presbyopic eyes.

Mechanism of Thymus Rejuvenation in Elderly Macaques.

Senile thymus atrophy is an important factor leading to decreased immune function. Repairing the atrophic thymus tissue structure, rebuilding immune function, and replenishing the number of exogenous stem cells may be ideal methods. In this study, bone marrow mesenchymal stem cells were intravenously infused into elderly macaques. We found that thymus volume was substantially increased, some thymus tissue regeneration was observed, the degree of thymus tissue fibrosis decreased, collagen fiber deposition decreased, cortical and medulla structures emerged gradually, the number of apoptotic cells decreased significantly, and the expression of apoptosis-related proteins decreased. For the effects of stem cell therapy on aging-related genes, we performed transcriptomic analysis of thymus tissue. The results show the expression pattern of the tissue transcriptome tended to be similar to the thymus expression pattern in young macaques compared with the elderly group, reverse aging-related proteins. Based on the results, it is suggested that stem cell therapy is an ideal method to prevent or reverse the aging of the thymus.

Analysis of SARS-CoV-2 pathogenicity in COVID-19 cynomolgus macaque model reflecting human COVID-19 pathological conditions

Abstract The pandemic of SARS-CoV-2 is still raging worldwide. Although rapid vaccination has been progressing in the world as a countermeasure against COVID-19, there are many issues regarding this disease including the emergence of variants and of their virulence that need to be elucidated, and a useful animal model is still necessary. We have established COVID-19 cynomolgus macaque (CM) model using healthy young CMs and CMs of advanced age (23 – 30 years of age, equivalent to 69 – 90 years of age in humans) with underlying diseases including diabetes and hyperlipidemia. There were differences between the pathological conditions in young macaques and elderly macaques of advanced age similar to observed in humans. In this study, we analyzed the virulence and pathology of SARS-CoV-2 variants of concern (VOCs) using COVID-19 CM model. Elucidation of how adaptive immunity in patients is induced by SARS-CoV-2 natural infection is critical for establishing a vaccine strategy, serologic therapies, public health control and prediction of infection. Therefore, we conducted the prolonged rechallenge analysis using COVID-19 CM model reinoculated with either the same or a different strain of SARS-CoV-2 that was used for the initial infection. Protective immunity against rechallenge of SARS-CoV-2 is under consideration, but in one elderly monkey reinfection showed transient pneumonia with increased levels of various serum cytokines and chemokines without detecting viruses in swab samples. Overall, the SARS-CoV-2-infected CM models reflected the pathology in humans, and studies using COVID-19 CM models should contribute to the elucidation of the complicated pathophysiology of COVID-19. Supported by grants from AMED (JP20fk0108414) and JSPS (21K19395)

Estimation of viral kinetics model parameters in young and aged SARS-CoV-2 infected macaques.

The SARS-CoV-2 virus disproportionately causes serious illness and death in older individuals. In order to have the greatest impact in decreasing the human toll caused by the virus, antiviral treatment should be targeted to older patients. For this, we need a better understanding of the differences in viral dynamics between SARS-CoV-2 infection in younger and older adults. In this study, we use previously published averaged viral titre measurements from the nose and throat of SARS-CoV-2 infection in young and aged cynomolgus macaques to parametrize a viral kinetics model. We find that all viral kinetics parameters differ between young and aged macaques in the nasal passages, but that there are fewer differences in parameter estimates from the throat. We further use our parametrized model to study the antiviral treatment of young and aged animals, finding that early antiviral treatment is more likely to lead to a lengthening of the infection in aged animals, but not in young animals.