2012年9月13日 电 /生物谷BIOON/ --近日，来自纽卡斯尔大学的研究者揭示了大脑神经元、神经细胞以及大脑其它部分变老的分子机制。相关成果刊登在了杂志Aging Cell上，该项研究为理解神经元如何衰老提供了一些思路，这或许为治疗如阿尔兹海默症等疾病带来一定帮助。
老化过程是我们机体细胞和分子固有的一种现象，以前有研究者识别出了一种分子途径可以和对细胞损伤产生反应，而且可以使得细胞进行分裂，俗称为细胞老化现象。然而有些细胞并不具有继续分裂的能力，就比如大脑中的神经元。如今，由教授Thomas von Zglinicki领导的这项研究揭示了大脑中的神经元同样也可以遵循细胞衰老的过程。
通过对特殊的年老老鼠进行研究，研究者发现了神经元的老化的确遵循了成纤维细胞开始衰老的规则，成纤维细胞可以在皮肤中进行分裂进而修复伤口。
DNA损伤的反应可以重新变成开始衰老的成纤维细胞，进而产生并且分泌出一种对宿主危险的物质，包括无氧自由基或者活性氧，并且可以促使信号分子的促炎症反应。这将使得衰老细胞不蹲损伤，最终被临近的正常细胞所替代。
如今，这项研究解释了神经元的衰老遵循着成纤维细胞衰老的规则。研究者von Zglinicki说，“我们需要发现，我们在小鼠大脑中检测到的机制是否人类的大脑衰老和认知力降低一样，这或许为理解大脑衰老的过程提供一定的思路。”（生物谷Bioon.com）
编译自：Discovering how the brain ages
doi:10.1111/j.1474-9726.2012.00870.x
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Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response
Diana Jurk1,†, Chunfang Wang2,†, Satomi Miwa1,†, Mandy Maddick1, Viktor Korolchuk1, Avgi Tsolou3, Efstathios S. Gonos3, Christopher Thrasivoulou4, M. Jill Saffrey2, Kerry Cameron1, Thomas von Zglinicki1
In senescent cells, a DNA damage response drives not only irreversible loss of replicative capacity but also production and secretion of reactive oxygen species (ROS) and bioactive peptides including pro-inflammatory cytokines. This makes senescent cells a potential cause of tissue functional decline in aging. To our knowledge, we show here for the first time evidence suggesting that DNA damage induces a senescence-like state in mature postmitotic neurons in vivo. About 40–80% of Purkinje neurons and 20–40% of cortical, hippocampal and peripheral neurons in the myenteric plexus from old C57Bl/6 mice showed severe DNA damage, activated p38MAPkinase, high ROS production and oxidative damage, interleukin IL-6 production, heterochromatinization and senescence-associated β-galactosidase activity. Frequencies of these senescence-like neurons increased with age. Short-term caloric restriction tended to decrease frequencies of positive cells. The phenotype was aggravated in brains of late-generation TERC−/− mice with dysfunctional telomeres. It was fully rescued by loss of p21(CDKN1A) function in late-generation TERC−/−CDKN1A−/− mice, indicating p21 as the necessary signal transducer between DNA damage response and senescence-like phenotype in neurons, as in senescing fibroblasts and other proliferation-competent cells. We conclude that a senescence-like phenotype is possibly not restricted to proliferation-competent cells. Rather, dysfunctional telomeres and/or accumulated DNA damage can induce a DNA damage response leading to a phenotype in postmitotic neurons that resembles cell senescence in multiple features. Senescence-like neurons might be a source of oxidative and inflammatory stress and a contributor to brain aging.
