Impaired autophagic function in rat islets with aging
Impaired autophagic function in rat islets with aging
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衰老大鼠胰岛自噬功能受损
DOI：
10.1007/s11357-012-9456-0
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发表时间：
2013-10-01
期刊：
影响因子：
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通讯作者：
Li, Chunlin
中科院分区：
文献类型：
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作者：
Liu, Yu;Shi, Suozhu;Li, Chunlin
2型糖尿病的特征在于β细胞功能和质量的缺陷，并且其发病率随着年龄的增长而增加。自噬是一种高度调节的细胞内过程，用于降解细胞质组分，特别是蛋白质聚集体和受损的细胞器。自噬受损或缺陷被认为会导致或促成衰老和年龄相关疾病。自噬可能是维持胰腺β细胞的结构、质量和功能所必需的。在这项研究中，我们研究了年龄对胰岛β细胞功能和自噬的影响，4个月大（年轻），14个月大（成年），24个月大（老年）雄性Wistar大鼠。我们发现胰岛β细胞功能随着年龄的增长而逐渐下降。自噬标志物LC 3/Atg8和Atg7的蛋白表达在老年胰岛中表现出显著下降。Lamp-2的表达，一个很好的自噬降解率的指标，在老年大鼠的胰岛中显著降低，表明自噬降解在老年大鼠的胰岛中减少。然而，beclin-1/Atg6的蛋白质表达，这起着重要的作用，在诱导和形成的前自噬体结构，通过与自噬调节蛋白（Atg14，Vps34/3类PI3激酶，和Vps15）的多聚体复合物，是最突出的成年大鼠的胰岛，并在24个月大的胰岛比4个月大的胰岛。p62/SQSTM 1和多聚泛素聚集体的水平，代表自噬和蛋白酶体降解的功能，在老化的胰岛中增加。8-羟基脱氧鸟苷，线粒体和核DNA氧化损伤的标志物，在老年胰岛中表现出强烈的免疫染色。电镜分析显示老年胰岛线粒体嵴肿胀、崩解。这些结果表明，胰岛中的β细胞和自噬功能随着Wistar大鼠年龄的增加而同时下降，并且老年大鼠胰岛中的自噬受损可能导致错误折叠和聚集的蛋白质的积累，并减少β细胞中异常线粒体的去除，导致β细胞功能降低。在衰老过程中胰岛中功能失调的自噬可能是导致2型糖尿病发展的重要机制。
Type 2 diabetes is characterized by a deficit in beta-cell function and mass, and its incidence increases with age. Autophagy is a highly regulated intracellular process for degrading cytoplasmic components, particularly protein aggregates and damaged organelles. Impaired or deficient autophagy is believed to cause or contribute to aging and age-related disease. Autophagy may be necessary to maintain structure, mass, and function of pancreatic beta-cells. In this study, we investigated the effects of age on beta-cell function and autophagy in pancreatic islets of 4-month-old (young), 14-month-old (adult), and 24-month-old (old) male Wistar rats. We found that islet beta-cell function decreased gradually with age. Protein expression of the autophagy markers LC3/Atg8 and Atg7 exhibited a marked decline in aged islets. The expression of Lamp-2, a good indicator of autophagic degradation rate, was significantly reduced in the islets of old rats, suggesting that autophagic degradation is decreased in the islets of aged rats. However, protein expression of beclin-1/Atg6, which plays an important role in the induction and formation of the pre-autophagosome structure by associating with a multimeric complex of autophagy regulatory proteins (Atg14, Vps34/class 3 PI3 kinase, and Vps15), was most prominent in the islets of adult rats, and was higher in 24-month-old islets than in 4-month-old islets. The levels of p62/SQSTM1 and polyubiquitin aggregates, representing the functions of autophagy and proteasomal degradation, were increased in aging islets. 8-Hydroxydeoxyguanosine, a marker of mitochondrial and nuclear DNA oxidative damage, exhibited strong immunostaining in old islets. Analysis by electron microscopy demonstrated swelling and disintegration of cristae in the mitochondria of aged islets. These results suggest that beta-cell and autophagic function in islets decline simultaneously with increasing age in Wistar rats, and that impaired autophagy in the islets of older rats may cause accumulation of misfolded and aggregated proteins and reduce the removal of abnormal mitochondria in beta-cells, leading to reduced beta-cell function. Dysfunctional autophagy in islets during the aging process may be an important mechanism leading to the development of type 2 diabetes.