Biology subjects

Kohama, S. G.

Publications and source records attributed to Kohama, S. G..

5 recordsLinked to original sources

bioRxiv2026

Sex-specific gene and isoform expression characterizes hippocampal aging in rhesus macaques

Aging produces widespread transcriptomic alterations that extend beyond changes in gene expression to include changes at the isoform level. Declining splicing fidelity, including increased intron retention and aberrant isoform expression, has been proposed to contribute to cellular dysfunction; however, the extent and biological significance of isoform-specific changes in the aging brain remain poorly understood. Age-related cognitive decline has also been associated with neuroinflammation and the development of a chronic inflammatory state, or ''inflammaging,'' within the brain. Here, we used short- and long-read RNA sequencing to characterize gene- and isoform-level changes associated with hippocampal aging across sex in 24 rhesus macaques. We identified 594 age-associated differential isoform expression events, comprising both shared and sex-specific changes. Inflammatory pathways, including TNF- -- NF-{kappa}B signaling, interferon responses, and complement pathways, were enriched across both sexes. Weighted gene co-expression network analysis (WGCNA) further identified sex-specific modules associated with inflammatory, glial, mitochondrial, and hormone-responsive processes. Notably, several age-associated changes were detected at the isoform level despite limited or absent corresponding gene-level differences, highlighting transcript-level regulation as an additional dimension of brain aging that may be overlooked by gene-level analyses. To investigate the relationship between aging and Alzheimer's disease (AD), we independently performed WGCNA on the rhesus macaque cohort and a publicly available human hippocampal AD single-nucleus RNA-sequencing dataset (GSE268609). Cross-species module preservation and gene overlap analyses identified shared genes between age-associated and AD-associated networks, with pathway enrichment implicating glial function, inflammation, and mitochondrial biology. Together, these findings highlight sex-associated differences in hippocampal transcriptomic aging, underscore the importance of isoform-level regulation, and identify shared transcriptional signatures between normal aging and AD-associated pathways.

neuroscience↗

bioRxiv2026

Aging macaques bridge the translational gap in perivascular space biology

The prevalence of MR-visible perivascular spaces (PVS) is age-dependent in rhesus macaques. Automated quantification in 94 male and female animals ranging 5-28 years of age demonstrated a robust association between age and PVS burden, with an anatomical distribution paralleling that of humans. Preliminary ex vivo validation confirmed that the MRI-detected tubular structures correspond to perivascular spaces. These findings establish the rhesus macaque as a tractable model for understanding the role of perivascular dysfunction in age-related brain vulnerability.

neuroscience↗

bioRxiv2023

Modulation of neural gene networks by estradiol in old rhesus macaque females.

The postmenopausal decrease in circulating estradiol (E2) levels has been shown to contribute to several adverse physiological and psychiatric effects. To elucidate the molecular effects of E2 on the brain, we examined differential gene expression and DNA methylation (DNAm) patterns in the nonhuman primate brain following ovariectomy (Ov) and subsequent E2 treatment. We identified several dysregulated molecular networks, including MAPK signaling and dopaminergic synapse response, that are associated with ovariectomy and shared across two different brain areas, the occipital cortex (OC) and prefrontal cortex (PFC). The finding that hypomethylation (p=1.6x10-51) and upregulation (p=3.8x10-3) of UBE2M across both brain regions, provide strong evidence for molecular differences in the brain induced by E2 depletion. Additionally, differential expression (p=1.9x10-4; interaction p=3.5x10-2) of LTBR in the PFC, provides further support for the role E2 plays in the brain, by demonstrating that the regulation of some genes that are altered by ovariectomy may also be modulated by Ov followed by hormone replacement therapy (HRT). These results present real opportunities to understand the specific biological mechanisms that are altered with depleted E2. Given E2s potential role in cognitive decline and neuroinflammation, our findings could lead to the discovery of novel therapeutics to slow cognitive decline. Together, this work represents a major step towards understanding molecular changes in the brain that are caused by ovariectomy and how E2 treatment may revert or protect against the negative neuro-related consequences caused by a depletion in estrogen as women approach menopause.

genetics↗

bioRxiv2023

Impact of aging on the immunological and microbial landscape of the lung during non-tuberculous mycobacterial infection

Nontuberculous mycobacteria (NTM) are environmentally ubiquitous and predominately cause pulmonary disease (NTMPD). The incidence of NTMPD has steadily increased and is now more prevalent than that of Mycobacterium tuberculosis (M. tb) in the US. Moreover, the prevalence of NTMPD increases with age; therefore, it is likely that the burden of NTMPD will continue to increase in the coming decades as the number of those over the age of 65 increased in the U.S population. However, the mechanisms leading to higher susceptibility and severity of NTMPD with aging are poorly defined. Here, we used a rhesus macaque model of intrabronchial infection with M. avium complex in young and aged animals to address this knowledge gap. Unilateral infection resulted in a robust inflammatory response predominantly in the inoculated lung, however, immune cell infiltration and antigen-specific T cell responses were detected in both lungs. Nasal, oral, and fecal swabs, and BAL samples were profiled using 16S amplicon sequencing. These data suggested that decompartmentalization of the lower respiratory microbiome was occurring, evidenced by detection of bacterial DNA typically found in the gut and oral-pharyngeal cavity in bronchoalveolar samples following infection. Radiographic studies, gross pathology, and histopathology examination revealed increased disease severity in aged compared to young animals with pulmonary consolidation, edema, and lesions. Finally, single cell RNA sequencing indicated that aged animals generated a dysregulated macrophage and CD8 T cell response to MAC infection.

immunology↗

bioRxiv2022

Functional, transcriptional, and microbial shifts associated with healthy pulmonary aging: insights from rhesus macaques

Older individuals are at increased risk of developing severe respiratory infections due to age-related changes in the immunological, microbial, and functional landscape of the lung. However, our understanding of the impact of age on the respiratory tract remains limited as samples from healthy humans are challenging to obtain and confounding variables such as smoking and environmental pollutant exposure make it difficult to assess the true impact of aging. On the other hand, studies in rodent models are biased by their specific pathogen free status. In this study, we utilize a rhesus macaque model of healthy aging to examine the functional, immunological, and microbial consequences of aging in the lung. Pulmonary function testing in this large (n=34 adult, n=49 aged) cross-sectional study established age and sex differences similar to humans supporting the translational accuracy of this model. Additionally, an increased abundance of myeloid cells (alveolar and infiltrating macrophages) and a concomitant decrease in T-cells were also observed in aged animals. Single cell RNA sequencing indicated a transcriptional shift in the pulmonary CD8+ T-cell population from GRZMB expressing cells to IFN expressing cells, while frequency of IL-1B expressing alveolar macrophages was significantly reduced. Interestingly, the lung microbiome of many animals was dominated by a single microbe, Tropheryma spp., the prevalence of which decreased with age. These data provide a comprehensive picture of the functional, microbial and immunological changes of the lung in healthy macaque aging and provide insight into the increased prevalence and severity of respiratory disease in the elderly.

immunology↗