The endocrine system plays a crucial role in regulating physiological processes and maintaining homeostasis. While previous studies have examined aging in individual endocrine organs, a comprehensive investigation across multiple endocrine tissues at single-cell resolution has been lacking. This study established the first single-cell aging atlas of the endocrine system, revealing conserved and organ-specific aging mechanisms while identifying novel regulatory pathways.
Key findings from the study include:
- Aging Regulatory Pathways in Functional Endocrine Cells: Single-cell transcriptomic analysis identified upregulation of hallmark aging pathways — including chronic inflammation, oxidative stress, protein homeostasis disruption, and cellular senescence — across multiple endocrine organs. Notably, enhanced unfolded protein response (UPR) was observed in thyroid, adrenal, and pituitary endocrine cells, suggesting protein homeostasis dysregulation as a key feature of endocrine aging.
- Discovery of the MHC-I-UPR Aging Axis: The study identified a novel MHC-I-UPR regulatory axis in endocrine cells, where elevated MHC-I expression triggered UPR activation. This axis represents a previously unrecognized mechanism linking immune signaling to cellular stress responses in aging endocrine tissues.
- Immune-Endocrine Crosstalk in Aging: Expanded populations of GZMK+CD8+ exhausted T cells were found to infiltrate aged endocrine organs. These cells promoted endocrine aging through GZMK-mediated activation of the MHC-I-UPR axis. Pharmacological inhibition of GZMK signaling with resatorvid and SCH79797 not only alleviated UPR and cellular senescence but also restored hormone levels in aged mice, demonstrating the functional reversibility of age-related endocrine decline.
- CD59 as a Novel Aging Biomarker: Machine learning analysis identified CD59 as a new molecular marker of aging in endocrine cells, providing a potential target for monitoring endocrine aging.
This study provides the first comprehensive single-cell atlas of endocrine aging, revealing both shared and organ-specific aging mechanisms. The findings not only advance understanding of endocrine aging but also suggest that immune-endocrine interactions represent a key node for potential interventions. Future studies will explore whether aged endocrine organs secrete systemic aging factors, potentially establishing endocrine tissues as central regulators of organismal aging. The work establishes a foundation for developing targeted strategies to maintain endocrine function during aging and potentially modulate systemic aging processes.
DOI:10.1093/procel/pwaf074