12404 Aging-Associated Decline in the Pituitary Gland Using Single-Cell Transcriptomes

Disclosure: Y. Kim: None. Introduction: Age-related decline in endocrine function has been associated with multiple physiological changes. However, aging-associated molecular shifts in the pituitary gland have not yet been systematically investigated. This study aimed to investigate the mechanism underlying these age-related molecular changes in young and old mice model using single cell transcriptomics. Method: Single-cell RNA sequencing (scRNA-seq) were conducted in young (2-month) and old (20-month) mouse. We used systems biology techniques to build a specific protein interaction network for somatotrophs, integrating validated interactions and gene expression data. By simulating drug effects on this network, we predicted changes in transcription factor activities due to aging. We identified potential therapeutic targets for preventing aging in somatotrophs by assessing the anti-aging effects of chemical perturbations, similar to methods used in the Connectivity Map project. Results: We identified 14 distinct cell types including follicular stellate cells (FSCs), somatotrophs, corticotrophs, gonadotrophs, lactotrophs, and melanotrophs. We found that the effect of aging on transcription was cell type dependent. FSC subtypes are heterogeneously regulated by aging at the transcriptomic level. However, somatotroph subtypes shared functional alterations with aging in terms of mRNA surveillance and spliceosome pathways. Our systems biology approach identified SENP1(Sentrin specific peptidase gene), as a critical node in the regulatory network affecting somatotroph aging. The senescence-associated beta-galactosidase staining (SAbgal) showed that Momordin (Mc), a SENP1 inhibitor, had anti-aging effects on somatotrophs, regardless of age-promoting doxorubicin. Western blot analysis indicated a two-fold increase in growth hormone levels in aged GH3 cells treated with Mc compared to vehicle. Conclusion: Our data and analysis provide promising resources to better understand the molecular shifts of pituitary aging at the transcriptomic level and help the community generate interesting hypotheses to develop anti-aging strategies for the pituitary gland. We suggest that SENP1 inhibitors may represent potential anti-aging targets in somatotroph. Presentation: 6/3/2024