Abstract
Aging plays a critical role in the progression of invasive neuroendocrine tumors (NETs) through mechanisms such as extracellular matrix remodeling, immune evasion, and cellular senescence. However, the influence of aging on pituitary neuroendocrine tumors (PitNETs) remains largely unexplored due to the absence of pituitary-specific aging studies. To address this gap, we investigated age-associated transcriptional changes in the normal pituitary as a foundation for understanding PitNET pathogenesis. Single-cell RNA sequencing (scRNA-seq) of pituitaries from young and aged mice revealed increased aging-associated gene (GAG) scores across all cell types, with somatotrophs showing the most prominent alterations. Given the critical role of somatotrophs in aging and their vulnerability, we constructed a somatotroph-specific protein-protein interaction (PPI) network to identify key molecular regulators of endocrine aging. Network analysis highlighted SENP1 and STAT3 signaling pathways as potential targets. To validate the anti-aging potential of SENP1 inhibition, we treated GH3 cells with a SENP1 inhibitor. Treatment reduced senescence markers regardless of doxorubicin exposure, indicating a broad anti-senescent effect. Notably, aged GH3 cells treated with the inhibitor showed increased growth hormone production compared to vehicle controls, whereas no significant changes were observed in young cells. These findings suggest that SENP1 inhibition may reverse age-associated endocrine decline in somatotrophs. Our results highlight the relevance of normal pituitary aging in tumor development and implicate mechanisms such as senescence-associated secretory phenotypes (SASPs) and hormonal axis dysregulation as potential drivers of PitNETs in the elderly. This study provides a molecular framework linking systemic aging to pituitary tumor biology and proposes the therapeutic repositioning of SENP1 inhibitors as a dual strategy targeting both aging and tumor progression in PitNETs.