Aging Impairs Adaptive Unfolded Protein Response and Drives Beta Cell Dedifferentiation in Humans.
Aging Impairs Adaptive Unfolded Protein Response and Drives Beta Cell Dedifferentiation in Humans.
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衰老会损害适应性未折叠蛋白反应并导致人类β细胞去分化
DOI：
10.1210/clinem/dgac535
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发表时间：
2022-11-25
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影响因子：
--
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中科院分区：
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糖尿病是一种与年龄相关的疾病;然而，衰老β细胞衰竭的潜在机制仍然未知。本研究的目的是调查是否以及如何通过排除糖耐量受损的影响，在衰老的人β细胞的分化状态被改变。我们计算了31名非糖尿病患者胰岛中FoxO 1和Urocortin 3的表达，并将其分为青年组（<40岁）、中年组（40-60岁）和老年组（>60岁）。我们还评估了衰老β细胞中的适应性未折叠蛋白反应标志物葡萄糖调节蛋白94（GRP 94）和剪接的X-box结合蛋白1（XBP 1 s）及其对维持β细胞身份和分化状态的可能贡献。我们发现老年组和中年组的去分化细胞比例比年轻组增加了近2倍（3.1 ± 1.0%和3.0 ± 0.9% vs 1.7 ± 0.5%，P <0.001）。这伴随着FoxO 1的失活和衰老的人β细胞中UCN 3表达的丧失。此外，我们证明了适应性未折叠蛋白反应（UPR）组分GRP 94和XBP 1 s的表达水平随着年龄的增长而下降。体外数据显示，在Min 6触发的细胞中敲低GRP 94以去分化并获得祖细胞特征，而在H2 O2诱导的衰老Min 6细胞中恢复GRP 94水平拯救了β细胞身份。我们的发现强调了在衰老的人类β细胞中未能建立适当的适应性UPR改变了它们的分化状态，这可能代表了与年龄相关的β细胞衰竭发病机制中的关键一步。
Diabetes is an age-related disease; however, the mechanism underlying senescent beta cell failure is still unknown. The present study was designed to investigate whether and how the differentiated state was altered in senescent human beta cells by excluding the effects of impaired glucose tolerance. We calculated the percentage of hormone-negative/chromogranin A–positive endocrine cells and evaluated the expressions of forkhead box O1 (FoxO1) and Urocortin 3 (UCN3) in islets from 31 nondiabetic individuals, divided into young (<40 years), middle-aged (40-60 years) and elderly (>60 years) groups. We also assessed adaptive unfolded protein response markers glucose-regulated protein 94 (GRP94), and spliced X-box binding protein 1 (XBP1s) in senescent beta cells and their possible contributions to maintaining beta cell identity and differentiation state. We found an almost 2-fold increase in the proportion of dedifferentiated cells in elderly and middle-aged groups compared with the young group (3.1 ± 1.0% and 3.0 ± 0.9% vs 1.7 ± 0.5%, P < .001). This was accompanied by inactivation of FoxO1 and loss of UCN3 expression in senescent human beta cells. In addition, we demonstrated that the expression levels of adaptive unfolded protein response (UPR) components GRP94 and XBP1s declined with age. In vitro data showed knockdown GRP94 in Min6-triggered cells to dedifferentiate and acquire progenitor features, while restored GRP94 levels in H2O2-induced senescent Min6 cells rescued beta cell identity. Our finding highlights that the failure to establish proper adaptive UPR in senescent human beta cells shifts their differentiated states, possibly representing a crucial step in the pathogenesis of age-related beta cell failure.
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影响因子：
64.5
作者：
Enge M;Arda HE;Mignardi M;Beausang J;Bottino R;Kim SK;Quake SR
通讯作者：
Quake SR
影响因子：
7.7
作者：
Gregg T;Poudel C;Schmidt BA;Dhillon RS;Sdao SM;Truchan NA;Baar EL;Fernandez LA;Denu JM;Eliceiri KW;Rogers JD;Kimple ME;Lamming DW;Merrins MJ
通讯作者：
Merrins MJ
影响因子：
4.1
作者：
Chan, Jeng Yie;Luzuriaga, Jude;Laybutt, D. Ross
通讯作者：
Laybutt, D. Ross
影响因子：
4.8
作者：
Kaneto, H;Xu, G;Weir, GC
通讯作者：
Weir, GC
DOI：
10.18632/aging.100350
发表时间：
2011-06
期刊：
Aging
影响因子：
--
作者：
Gunasekaran U;Gannon M
通讯作者：
Gannon M