Progressive impairment of proteostasis and accumulation of toxic misfolded proteins are associated with the cellular aging process. Here, we employed chronologically aged yeast cells to investigate how activation of the unfolded protein response (UPR) upon accumulation of misfolded proteins in the endoplasmic reticulum (ER) affects lifespan. We found that cells lacking a functional UPR display a significantly reduced chronological lifespan, which contrasts previous findings in models of replicative aging. We find exacerbated UPR activation in aged cells, indicating an increase in misfolded protein burden in the ER during the course of aging. We also observed that caloric restriction, which promotes longevity in various model organisms, extends lifespan of UPR-deficient strains. Similarly, aging in pH-buffered media extends lifespan, albeit independently of the UPR. Thus, our data support a role for caloric restriction and reduced acid stress in improving ER homeostasis during aging. Finally, we show that UPR-mediated upregulation of the ER chaperone Kar2 and functional ER-associated degradation (ERAD) are essential for proper aging. Our work documents the central role of secretory protein homeostasis in chronological aging in yeast and highlights that the requirement for a functional UPR can differ between post-mitotic and actively dividing eukaryotic cells.

中文翻译：

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酿酒酵母中按时间顺序老化需要功能性的未折叠蛋白质反应。

蛋白变性的逐步损伤和有毒的错误折叠蛋白的积累与细胞衰老过程有关。在这里，我们采用了按时间顺序老化的酵母细胞，以研究错误折叠的蛋白质在内质网（ER）中积累后未折叠的蛋白质应答（UPR）的激活如何影响寿命。我们发现缺少功能性UPR的细胞显示出明显的时间寿命缩短，这与复制性衰老模型中的先前发现形成对比。我们发现衰老细胞中的UPR活化加剧，表明衰老过程中ER中折叠错误的蛋白质负担增加。我们还观察到热量限制会促进各种模式生物的寿命，从而延长了UPR缺陷菌株的寿命。同样，在pH缓冲液中老化会延长使用寿命，尽管独立于普遍定期审议。因此，我们的数据支持热量限制和减少酸应激在改善衰老过程中ER稳态中的作用。最后，我们表明，ER伴侣Kar2的UPR介导的上调和功能性ER相关降解（ERAD）对于适当的衰老至关重要。我们的工作记录了分泌蛋白动态平衡在酵母中按时间顺序老化的重要作用，并强调功能性UPR的需求在有丝分裂后的和活跃分裂的真核​​细胞之间可能有所不同。