Abstract

Aging-related degeneration of pancreatic islet cells contributes to impaired glucose tolerance and diabetes. Endocrine cells age heterogeneously, complicating the efforts to unravel the molecular drivers 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 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 pathways, comprising adaptive UPR during pancreatic aging. Notably, we found aging-related β-cell-specific upregulation of HSP90B1, an endoplasmic reticulum-located chaperone, impeded high glucose-induced insulin secretion. Our work decodes aging-associated transcriptomic changes that underlie pancreatic islet functional decay at single-cell resolution and indicates that targeting UPR components may prevent loss of proteostasis, suggesting an avenue to delaying β-cell aging and preventing aging-related diabetes.

中文翻译：

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灵长类胰岛衰老的单细胞转录组图谱

摘要

胰岛细胞的衰老相关变性导致糖耐量受损和糖尿病。内分泌细胞的衰老是异质的，这使得解开内分泌衰老背后的分子驱动因素的努力变得复杂。为了克服这些障碍，我们对从年轻和年老的非糖尿病食蟹猴中获得的胰岛细胞进行了单细胞 RNA 测序。尽管存在性别差异和转录变异增加，但老化的 β 细胞显示出未折叠蛋白反应 (UPR) 增加以及蛋白质聚集体的积累。我们观察到与经典 ATF6 和 IRE1 信号通路相关的 UPR 成分的转录组失调，包括胰腺衰老过程中的适应性 UPR。值得注意的是，我们发现 HSP90B1（一种位于内质网的分子伴侣）与衰老相关的 β 细胞特异性上调，阻碍高糖诱导的胰岛素分泌。我们的工作在单细胞分辨率下解码了导致胰岛功能衰退的衰老相关转录组变化，并表明靶向 UPR 成分可以防止蛋白质稳态的丧失，这表明了延缓 β 细胞衰老和预防衰老相关糖尿病的途径。