Splicing factor 1 modulates dietary restriction and TORC1 pathway longevity in C. elegans.
Splicing factor 1 modulates dietary restriction and TORC1 pathway longevity in C. elegans.
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DOI：
10.1038/nature20789
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发表时间：
2017-01-05
期刊：
影响因子：
64.8
通讯作者：
Mair WB
中科院分区：
文献类型：
--
作者：
Heintz C;Doktor TK;Lanjuin A;Escoubas C;Zhang Y;Weir HJ;Dutta S;Silva-García CG;Bruun GH;Morantte I;Hoxhaj G;Manning BD;Andresen BS;Mair WB
衰老是由转录和蛋白质稳态的丧失驱动的，是多种慢性疾病的关键风险因素。因此，随着年龄的增长，减轻或逆转全身功能障碍的干预措施有可能降低老年人的总体疾病风险。前体mRNA剪接是基因表达和蛋白质组之间的基本联系，剪接机制的失调与多种年龄相关的慢性疾病有关。然而，剪接稳态在健康老龄化中的作用仍不清楚。在这里，我们表明，前mRNA剪接稳态是秀丽隐杆线虫的生物标志物和预期寿命的预测。使用转录组学和深入的剪接分析，在年轻和年老的动物喂养随意或饮食限制（DR），我们发现缺陷的全球前mRNA剪接随着年龄的减少DR通过分支点结合蛋白（BBP）/剪接因子1（SFA-1）。我们发现SFA-1是DR延长寿命和调节TORC 1通路组分AMPK、RAGA-1和RSKS-1/S6激酶所特别需要的。最后，我们证明了SFA-1的过表达足以延长寿命。总之，这些数据证明了RNA剪接稳态在DR寿命中的作用，并表明特定剪接体组分的调节可以延长健康衰老。
Ageing is driven by a loss of transcriptional and protein homeostasis and is the key risk factor for multiple chronic diseases. Interventions that attenuate or reverse systemic dysfunction seen with age therefore have potential to reduce overall disease risk in the elderly. Pre-mRNA splicing is a fundamental link between gene expression and the proteome, and deregulation of the splicing machinery is linked to multiple age-related chronic diseases. However, the role of splicing homeostasis in healthy ageing remains unclear. Here we demonstrate that pre-mRNA splicing homeostasis is a biomarker and predictor of life expectancy in Caenorhabditis elegans. Using transcriptomics and in-depth splicing analysis in young and old animals fed ad libitum or on dietary restriction (DR), we find defects in global pre-mRNA splicing with age that are reduced by DR via the branch point binding protein (BBP)/splicing factor 1 (SFA-1). We show that SFA-1 is specifically required for lifespan extension both by DR, and modulation of TORC1 pathway components AMPK, RAGA-1 and RSKS-1/S6 Kinase. Lastly, we demonstrate that overexpression of SFA-1 is sufficient to extend lifespan. Together, these data demonstrate a role for RNA splicing homeostasis in DR longevity and suggest modulation of specific spliceosome components can prolong healthy ageing.