A mechanistic study of anti-ageing interventions in translation

众所周知，衰老是一个可塑的过程，对一系列细胞过程的干预可以延长寿命和健康寿命。翻译就是这样一个过程，在解码阶段提高翻译保真度已被证明可以延长寿命，相反，降低保真度已被证明会缩短寿命。许多因素已经被证明可以调节这种保真度，包括翻译伸长的减慢，翻译因子的抑制，以及在RPS23中引入点突变；核糖体蛋白尽管有这些观察结果，但这些改变提高翻译保真度从而延长寿命的具体机制尚未确定。在这个项目中，生化分析，如双荧光素酶报告分析，结构生物学技术，包括低温电子显微镜和质谱，将被用来精确地确定这些干预是如何改变翻译机制的。有了这种机制和结构知识基础，就有可能研究和设计小分子药物和抑制剂，这些药物和抑制剂可以概括这些延长寿命的作用，为延长寿命提供可行的手段，更重要的是，可能延长个人的健康预期寿命。

Ageing is known to be a malleable process, with interventions in a range of cellular processes leading to extended lifespans and healthspans. Translation is one such process in which improved translational fidelity at the stage of decoding has been shown to extend lifespans, and conversely reduced fidelity has been shown to decrease lifespans. Many factors have been shown to modulate this fidelity including the slowing of translation elongation, the inhibition of translation factors, and the introduction of point mutations into RPS23; a ribosomal protein. Despite these observations, the specific mechanisms by which these alterations improve translational fidelity and thus lifespans have not been determined. During this project, biochemical assays such as dual luciferase reporter assays, and structural biology techniques including cryo-electron microscopy and mass spectrometry will be used to ascertain precisely how these interventions alter the translational machinery. With this mechanistic and structural knowledge base it may then be possible to investigate and design small molecule drugs and inhibitors that can recapitulate these life extending effects providing a viable means for improving lifespans and potentially more importantly, an individual's healthy life expectancy.