National Research Council of Italy, Institute of Molecular Genetics, Unit of Bologna IOR, 40136 Bologna, Italy.
J Cell Sci. 2014 Jan 1;127(Pt 1):147-57. doi: 10.1242/jcs.133983. Epub 2013 Oct 23.
The dynamic organisation of the cell nucleus is profoundly modified during growth, development and senescence as a result of changes in chromatin arrangement and gene transcription. A plethora of data suggests that the nuclear lamina is a key player in chromatin dynamics and argues in favour of a major involvement of prelamin A in fundamental mechanisms regulating cellular senescence and organism ageing. As the best model to analyse the role of prelamin A in normal ageing, we used cells from centenarian subjects. We show that prelamin A is accumulated in fibroblasts from centenarians owing to downregulation of its specific endoprotease ZMPSTE24, whereas other nuclear envelope constituents are mostly unaffected and cells do not enter senescence. Accumulation of prelamin A in nuclei of cells from centenarians elicits loss of heterochromatin, as well as recruitment of the inactive form of 53BP1, associated with rapid response to oxidative stress. These effects, including the prelamin-A-mediated increase of nuclear 53BP1, can be reproduced by rapamycin treatment of cells from younger individuals. These data identify prelamin A and 53BP1 as new targets of rapamycin that are associated with human longevity. We propose that the reported mechanisms safeguard healthy ageing in humans through adaptation of the nuclear environment to stress stimuli.
细胞核的动态组织在生长、发育和衰老过程中会发生深刻的改变，这是由于染色质排列和基因转录的变化所致。大量数据表明核纤层是染色质动力学的关键参与者，并支持 prelamin A 在前体细胞衰老和生物体衰老的基本机制中发挥主要作用。作为分析 prelamin A 在正常衰老中作用的最佳模型，我们使用了来自百岁老人的细胞。我们发现，由于其特异性内切酶 ZMPSTE24 的下调，prelamin A 在来自百岁老人的成纤维细胞中积累，而其他核膜成分大多不受影响，细胞也不会进入衰老状态。来自百岁老人的细胞的细胞核中 prelamin A 的积累会导致异染色质的丢失，以及无活性形式的 53BP1 的募集，这与对氧化应激的快速反应有关。这些效应，包括核 53BP1 的 prelamin-A 介导的增加，可以通过雷帕霉素处理年轻个体的细胞来重现。这些数据将 prelamin A 和 53BP1 鉴定为与人类长寿相关的雷帕霉素的新靶标。我们提出，所报道的机制通过核环境对应激刺激的适应来保护人类的健康衰老。
