Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158, USA.
J Neurosci. 2011 Jun 22;31(25):9279-88. doi: 10.1523/JNEUROSCI.6606-10.2011.
The analysis of morphological changes that occur in the nervous system during normal aging could provide insight into cognitive decline and neurodegenerative disease. Previous studies have suggested that the nervous system of Caenorhabditis elegans maintains its structural integrity with age despite the deterioration of surrounding tissues. Unexpectedly, we observed that neurons in aging animals frequently displayed ectopic branches and that the prevalence of these branches increased with time. Within age-matched populations, the branching of mechanosensory neurons correlated with decreased response to light touch and decreased mobility. The incidence of branching was influenced by two pathways that can affect the rate of aging, the Jun kinase pathway and the insulin/IGF-1 pathway. Loss of Jun kinase signaling, which slightly shortens lifespan, dramatically increased and accelerated the frequency of neurite branching. Conversely, inhibition of the daf-2 insulin/IGF-1-like signaling pathway, which extends lifespan, delayed and suppressed branching, and this delay required DAF-16/FOXO activity. Both JNK-1 and DAF-16 appeared to act within neurons in a cell-autonomous manner to influence branching, and, through their tissue-specific expression, it was possible to disconnect the rate at which branching occurred from the overall rate of aging of the animal. Old age has generally been associated with the decline and deterioration of different tissues, except in the case of tumor cell growth. To our knowledge, this is the first indication that aging can potentiate another form of growth, the growth of neurite branches, in normal animals.
分析正常衰老过程中神经系统发生的形态变化，可以深入了解认知能力下降和神经退行性疾病。先前的研究表明，尽管周围组织恶化，秀丽隐杆线虫的神经系统仍能保持其结构完整性。出乎意料的是，我们观察到衰老动物的神经元经常出现异位分支，并且这些分支的出现频率随着时间的推移而增加。在年龄匹配的群体中，机械感觉神经元的分支与对轻触的反应减弱和运动能力下降有关。分支的发生率受到两种途径的影响，这两种途径可以影响衰老的速度，即 Jun 激酶途径和胰岛素/IGF-1 途径。Jun 激酶信号通路的丧失（略微缩短寿命）显著增加并加速了神经突分支的频率。相反，抑制 daf-2 胰岛素/IGF-1 样信号通路（延长寿命）会延迟和抑制分支，这种延迟需要 DAF-16/FOXO 活性。JNK-1 和 DAF-16 似乎都以细胞自主的方式在神经元中发挥作用，影响分支，并且通过其组织特异性表达，可以将分支发生的速度与动物的整体衰老速度脱钩。一般来说，老年与不同组织的衰退和恶化有关，肿瘤细胞生长除外。据我们所知，这是衰老可以增强正常动物另一种形式的生长（神经突分支的生长）的第一个迹象。
