Negligible senescence in naked mole rats may be a consequence of well-maintained splicing regulation
Negligible senescence in naked mole rats may be a consequence of well-maintained splicing regulation
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DOI：
10.1007/s11357-019-00150-7
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发表时间：
2020-04-01
期刊：
影响因子：
5.6
通讯作者：
Harries, L. W.
中科院分区：
文献类型：
--
作者：
Lee, B. P.;Smith, M.;Harries, L. W.
裸鼹鼠（nmr）相对于任何已知的非volant哺乳动物物种的身体大小具有最长的寿命。它们还表现出增强的抗应激表型，衰老可以忽略不计，并且很少患有与年龄有关的慢性疾病。选择性剪接（AS）失调正在成为衰老和老化的潜在驱动因素。我们假设，剪接因子的表达，AS模式的重要监管机构，可能会有所不同的NMR相比，其他物种的寿命相对较短。我们设计了特定于NMR剪接调节因子的检测方法，也设计了一组预先选择的脑表达基因，这些基因已知在其他物种中表现出AS的衰老相关改变，并使用胚胎和新生儿发育阶段测量了这些转录物表达水平的年龄相关变化，直至NMR脑样本中的极端老年。我们还比较了年轻小鼠和核磁共振脾和脑样品中剪接因子的表达。两种NMR组织均显示出在来自相似大小的小鼠的组织中观察到的表达水平的大约两倍。此外，与其他物种的观察结果相反，在生命早期阶段短暂的不稳定表达后，成人NMR剪接因子和AS模式的功能相关的脑基因保持显着稳定至少二十年。这些发现与一个模型是一致的，即剪接调控和AS的稳定模式的保护可能有助于更好的分子应激反应和避免NMR衰老，有助于其特殊的寿命和延长的健康寿命。
Naked mole-rats (NMRs) have amongst the longest lifespans relative to body size of any known, non-volant mammalian species. They also display an enhanced stress resistance phenotype, negligible senescence and very rarely are they burdened with chronic age-related diseases. Alternative splicing (AS) dysregulation is emerging as a potential driver of senescence and ageing. We hypothesised that the expression of splicing factors, important regulators of patterns of AS, may differ in NMRs when compared to other species with relatively shorter lifespans. We designed assays specific to NMR splicing regulatory factors and also to a panel of pre-selected brain-expressed genes known to demonstrate senescence-related alterations in AS in other species, and measured age-related changes in the transcript expression levels of these using embryonic and neonatal developmental stages through to extreme old age in NMR brain samples. We also compared splicing factor expression in both young mouse and NMR spleen and brain samples. Both NMR tissues showed approximately double the expression levels observed in tissues from similarly sized mice. Furthermore, contrary to observations in other species, following a brief period of labile expression in early life stages, adult NMR splicing factors and patterns of AS for functionally relevant brain genes remained remarkably stable for at least two decades. These findings are consistent with a model whereby the conservation of splicing regulation and stable patterns of AS may contribute to better molecular stress responses and the avoidance of senescence in NMRs, contributing to their exceptional lifespan and prolonged healthspan.