Single-cell transcriptomic analysis reveals that inflammation drives the unfolded protein response during endocrine aging in mice

The endocrine system severely impacts individual aging. However, its cellular signatures and underlying mechanisms have not been comprehensively elucidated. Here, we present a comprehensive single-cell transcriptomic atlas of six endocrine tissues from young and aged mice. Multiple aging-related pathways are disrupted in endocrine tissues, and the unfolded protein response (UPR) emerged as a key pathway related to endocrine aging. We found significant age-related expansion of exhausted GZMK+CD8+ T cells within endocrine tissues. Additionally, granzyme K (GZMK) signaling enhances the UPR and accelerates cellular senescence through the modulation of MHC-I expression in functional endocrine cells, revealing a novel regulatory axis of aging. Moreover, the inhibition of the GZMK receptor counteracts the UPR and endocrine aging. These findings establish an interplay between inflammation and the UPR in endocrine aging, offering profound insights into the underlying mechanisms of endocrine aging. Overall design: We isolated the hypothalamus, pituitary glands, thyroid glands, adrenal glands, pancreas islets, and pineal glands from aged mice and young mice.