Replication Data for: The unfolded protein response reverses the effects of glucose on lifespan in chemically-sterilized C. elegans

Metabolic diseases often share common traits, including accumulation of unfolded proteins in the endoplasmic reticulum (ER). Upon ER stress, the unfolded protein response (UPR) is activated to limit cellular damage which weakens with age. Here, we show that Caenorhabditis elegans fed a bacterial diet with high glucose diet at day 5 of adulthood (HGD-5) extends their lifespan, whereas exposed at day 1 (HGD-1) experience shortened longevity. We observed a metabolic shift only in HGD-1, while glucose and infertility synergistically prolonged the lifespan of HGD-5, independently of DAF-16. Notably, we identified that UPR stress sensors ATF-6 and PEK-1 contributed to the longevity of HGD-5 worms, while ire-1 ablation drastically increased HGD-1 lifespan. Together, we postulate that HGD activates the otherwise quiescent UPR in aged worms to overcome ageing-related stress and restore ER homeostasis. In contrast, young animals subjected to HGD provokes unresolved ER stress, conversely leading to a detrimental stress response.

代谢性疾病通常具有共同病理特征，包括内质网（endoplasmic reticulum, ER）内未折叠蛋白的蓄积。当发生内质网应激时，未折叠蛋白反应（unfolded protein response, UPR）会被激活以限制细胞损伤，而该保护机制会随衰老进程逐渐减弱。本研究发现，在成虫第5天喂食含高糖细菌饮食的秀丽隐杆线虫（Caenorhabditis elegans，以下简称线虫）（HGD-5）的寿命得以延长，而在成虫第1天即暴露于该高糖饮食的线虫（HGD-1）寿命则显著缩短。研究仅在HGD-1组线虫中观察到代谢重编程现象；高糖与不育状态可协同延长HGD-5组线虫的寿命，且该调控过程不依赖DAF-16。值得注意的是，本研究证实UPR应激传感器ATF-6与PEK-1参与介导HGD-5组线虫的长寿表型，而敲除ire-1可显著延长HGD-1组线虫的寿命。综上，我们推测高糖饮食会激活衰老线虫中原本处于静息状态的UPR，以对抗衰老相关应激并恢复ER稳态。与之相反，年轻线虫暴露于高糖饮食则会引发未解决的内质网应激，进而诱发有害的应激反应。