Institute of Healthy Ageing, Research Department of Genetics, Evolution and Environment, University College London, London, WC1E 6BT, UK.
Institute of Clinical Sciences, Imperial College London, London, W12 0NN, UK.
EMBO Rep. 2024 Nov;25(11):4921-4949. doi: 10.1038/s44319-024-00265-9. Epub 2024 Oct 2.
Genomes produce widespread long non-coding RNAs (lncRNAs) of largely unknown functions. We characterize aal1 (ageing-associated lncRNA), which is induced in quiescent fission yeast cells. Deletion of aal1 shortens the chronological lifespan of non-dividing cells, while ectopic overexpression prolongs their lifespan, indicating that aal1 acts in trans. Overexpression of aal1 represses ribosomal-protein gene expression and inhibits cell growth, and aal1 genetically interacts with coding genes functioning in protein translation. The aal1 lncRNA localizes to the cytoplasm and associates with ribosomes. Notably, aal1 overexpression decreases the cellular ribosome content and inhibits protein translation. The aal1 lncRNA binds to the rpl1901 mRNA, encoding a ribosomal protein. The rpl1901 levels are reduced ~2-fold by aal1, which is sufficient to extend lifespan. Remarkably, the expression of the aal1 lncRNA in Drosophila boosts fly lifespan. We propose that aal1 reduces the ribosome content by decreasing Rpl1901 levels, thus attenuating the translational capacity and promoting longevity. Although aal1 is not conserved, its effect in flies suggests that animals feature related mechanisms that modulate ageing, based on the conserved translational machinery.
基因组产生广泛的长非编码 RNA(lncRNA),其功能在很大程度上是未知的。我们对 aal1(与衰老相关的 lncRNA)进行了研究,该基因在静止的裂殖酵母细胞中被诱导表达。aal1 的缺失缩短了非分裂细胞的程序性衰老寿命,而过表达则延长了它们的寿命,这表明 aal1 具有转位作用。aal1 的过表达抑制了核糖体蛋白基因的表达并抑制了细胞生长,并且 aal1 在遗传上与编码参与蛋白质翻译的基因相互作用。aal1 lncRNA 定位于细胞质并与核糖体结合。值得注意的是,aal1 的过表达会降低细胞核糖体含量并抑制蛋白质翻译。aal1 lncRNA 与编码核糖体蛋白的 rpl1901 mRNA 结合。aal1 使 rpl1901 的水平降低了约 2 倍,这足以延长寿命。值得注意的是,aal1 lncRNA 在果蝇中的表达可提高果蝇的寿命。我们提出,aal1 通过降低 Rpl1901 水平来减少核糖体含量,从而减弱翻译能力并促进长寿。尽管 aal1 没有保守性,但它在果蝇中的作用表明,动物具有基于保守的翻译机制来调节衰老的相关机制。