Department of Anatomy and Cell Biology, The University of Western Ontario, London, N6A 5C1, Canada.
Department of Biochemistry, The University of Western Ontario, London, N6A 5C1, Canada.
Curr Genet. 2020 Feb;66(1):263-277. doi: 10.1007/s00294-019-01019-0. Epub 2019 Jul 25.
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.
蛋白质稳态的逐渐受损和有毒错误折叠蛋白质的积累与细胞衰老过程有关。在这里，我们使用经过时间老化的酵母细胞来研究内质网（ER）中错误折叠蛋白质积累时未折叠蛋白反应（UPR）的激活如何影响寿命。我们发现，缺乏功能 UPR 的细胞表现出明显缩短的时序寿命，这与复制性衰老模型中的先前发现形成对比。我们在老化细胞中发现了加剧的 UPR 激活，表明在衰老过程中 ER 中错误折叠蛋白负担增加。我们还观察到，在各种模式生物中促进长寿的热量限制延长了 UPR 缺陷菌株的寿命。同样，在 pH 缓冲培养基中老化虽然独立于 UPR，但也延长了寿命。因此，我们的数据支持热量限制和减少酸应激在衰老过程中改善 ER 动态平衡的作用。最后，我们表明 UPR 介导的 ER 伴侣 Kar2 的上调和功能性 ER 相关降解（ERAD）对于正常衰老至关重要。我们的工作证明了分泌蛋白稳态在酵母中的时序衰老中的核心作用，并强调了功能 UPR 的需求在有丝分裂后和活跃分裂的真核细胞之间可能不同。
