Loss of proteostasis is a fundamental process driving aging. Proteostasis is affected by the accuracy of translation, yet the physiological consequence of having fewer protein synthesis errors during multi-cellular organismal aging is poorly understood. Our phylogenetic analysis of RPS23, a key protein in the ribosomal decoding center, uncovered a lysine residue almost universally conserved across all domains of life, which is replaced by an arginine in a small number of hyperthermophilic archaea. When introduced into eukaryotic RPS23 homologs, this mutation leads to accurate translation, as well as heat shock resistance and longer life, in yeast, worms, and flies. Furthermore, we show that anti-aging drugs such as rapamycin, Torin1, and trametinib reduce translation errors, and that rapamycin extends further organismal longevity in RPS23 hyperaccuracy mutants. This implies a unified mode of action for diverse pharmacological anti-aging therapies. These findings pave the way for identifying novel translation accuracy interventions to improve aging.

蛋白质稳态的丧失是驱动衰老的一个基本过程。蛋白质稳态受翻译准确性的影响，但人们对多细胞机体衰老过程中蛋白质合成错误较少的生理后果知之甚少。我们对核糖体解码中心的关键蛋白 RPS23 的系统发育分析发现，赖氨酸残基在所有生命领域几乎普遍保守，在少数超嗜热古菌中被精氨酸取代。当引入真核 RPS23 同系物时，这种突变会在酵母、蠕虫和果蝇中产生准确的翻译，以及抗热激性和更长的寿命。此外，我们表明抗衰老药物如雷帕霉素、Torin1 和曲美替尼可减少翻译错误，并且雷帕霉素进一步延长了 RPS23 超精确突变体的机体寿命。这意味着不同药物抗衰老疗法的统一作用模式。这些发现为确定新的翻译准确性干预措施以改善衰老铺平了道路。