A single-cell transcriptomic landscape characterizes the endocrine system aging in the mouse

The endocrine system is crucial for maintaining overall homeostasis. However, its cellular signatures have not been elucidated during aging. Here, we conducted the first-ever single-cell transcriptomic profiles from eight endocrine organs in young and aged mice, revealing the activation of cell-type-specific aging pathways, such as loss of proteostasis, genomic instability and reactive oxygen species (ROS). Among six sex-shared endocrine organs, aging severely impaired gene expression networks in functional endocrine cells, accompanied by enhanced immune infiltration and unfolded protein response (UPR). Mechanism investigations showed that expanded aging-associated exhausted T cells activated MHC-I–UPR axis across functional endocrine cells by releasing GZMK. The inhibition of GZMK receptors by small chemical molecules counteracted the UPR and senescence, suggesting the immune infiltration is a possible driver of endocrine aging. Machine learning identified CD59 as a novel aging feature in sex-shared functional endocrine cells. For two sex-specific endocrine organs, both aged ovaries and testes showed enhanced immune responses. Meanwhile, cell-type-specific aging-associated transcriptional changes revealed an enhanced ROS mainly in aged theca cells of ovaries, while aged spermatogonia in testes showed impaired DNA repair. This study provides a comprehensive analysis of endocrine system aging at single-cell resolution, offering profound insights into mechanisms of endocrine aging.