Aging-related degeneration of pancreatic islet cells contributes to impaired glucose tolerance and diabetes. Endocrine cells age heterogeneously, complicating the effort to unravel the molecular drives underlying endocrine aging. To overcome these obstacles, we undertook single-cell RNA sequencing of pancreatic islet cells obtained from young and aged non-diabetic cynomolgus monkeys. Despite sex differences and increased single-cell level transcriptional variations, aged β-cells showed increased unfolded protein response (UPR) along with the accumulation of protein aggregates. We observed transcriptomic dysregulation of UPR components linked to canonical ATF6 and IRE1 signaling, comprising adaptive UPR during pancreatic aging. Notably, we found age-related β-cell-specific upregulation of HSP90B1, an ER-located chaperone, impeded high glucose-induced insulin secretion. Our work decodes aging-associated transcriptomic changes that underlie pancreatic islet functional decay at the single-cell resolution and indicates that targeting UPR components may prevent loss of proteostasis, suggesting an avenue for therapies to delay β-cell aging and prevent aging-related diabetes.
Overall design: We collected ~5,000 single cells from the pancreas of 8 young and 8 aged monkeys and performed single-cell RNA-seq sequencing.
[Correspondences between file labels and monkey individuals]
CE01: YF1, CE07: YF2, CE08: YF3, CE14: YF4
CE04: YM1, CE05: YM2, CE06: YM3, CE15: YM4
CE09: OF1, CE10: OF2, CE13: OF3, CE16: OF4
CE03: OM1, CE11: OM2, CE12: OM3, CE17: OM4
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