范德比尔特大学医学院Kristopher Burkewitz团队近日取得一项新成果。经过不懈努力，他们发现了内质网重塑是衰老的一个特征，依赖于内质网吞噬。相关论文发表在2026年2月2日出版的《自然—细胞生物学》杂志上。

在这里，小组将内质网结构和功能重塑作为酵母、秀丽隐杆线虫和哺乳动物衰老的保守特征。将秀丽隐杆线虫作为后生动物衰老的典型，课题组揭示了不同组织中内质网体积的显著年龄相关减少以及从粗糙片到管状内质网的形态转变。这种形态转变与内质网蛋白质组组成从蛋白质合成到脂质代谢的大规模转变相对应，这是哺乳动物组织中保守的现象。小组发现Atg8和ULK1依赖的ER吞噬通过组织特异性因子驱动年龄相关的ER重塑，包括以前未表征的ER吞噬调节因子TMEM-131和未折叠蛋白反应的IRE-1-XBP-1分支。为一个模型提供支持，其中内质网重构是适应性的，多样化的寿命延长范例，并在整个生命过程中重构内质网形态。

此外，酵母和蠕虫中依赖mTOR的寿命延长需要ER吞噬，这表明ER重塑是衰老过程中的一种主动和保护性反应。这些结果表明，内质网吞噬和内质网动力学是正常衰老和延缓衰老干预措施中明显的、未被充分认识的机制。

研究人员表示，内质网（ER）由一系列子结构域组成，每个子结构域由一个特征结构和功能定义。尽管内质网过程的改变与年龄发病机制有关，但尚不清楚内质网结构或动力学的变化是否导致了这些功能变化。

附：英文原文

Title: ER remodelling is a feature of ageing and depends on ER-phagy

Author: Donahue, Eric K. F., Hepowit, Nathaniel L., Ruark, Elizabeth M., Mulligan, Alexandra G., Keuchel, Brennen, Urban, Nicholas D., Peng, Li, Stephens, Stedman, Johnson, Derek J., Wallace, Natalie S., Jackson, Lauren P., Ellisman, Mark H., Arrojo e Drigo, Rafael, Folkmann, Andrew W., Truttmann, Matthias C., MacGurn, Jason A., Burkewitz, Kristopher

Issue&Volume: 2026-02-02

Abstract: The endoplasmic reticulum (ER) comprises an array of subdomains, each defined by a characteristic structure and function. Although altered ER processes are linked to age-onset pathogenesis, it is unclear whether shifts in ER structure or dynamics underlie these functional changes. Here we establish ER structural and functional remodelling as a conserved feature of ageing across yeast, Caenorhabditis elegans and mammals. Focusing on C. elegans as the exemplar of metazoan ageing, we reveal striking age-related reductions in ER volume across diverse tissues and a morphological shift from rough sheets to tubular ER. This morphological transition corresponds with large-scale shifts in ER proteome composition from protein synthesis to lipid metabolism, a phenomenon conserved in mammalian tissues. We show that Atg8 and ULK1-dependent ER-phagy drives age-associated ER remodelling through tissue-specific factors, including the previously uncharacterized ER-phagy regulator TMEM-131 and the IRE-1–XBP-1 branch of the unfolded protein response. Providing support for a model where ER remodelling is adaptive, diverse lifespan-extending paradigms downscale and remodel ER morphology throughout life. Furthermore, mTOR-dependent lifespan extension in yeast and worms requires ER-phagy, indicating that ER remodelling is a proactive and protective response during ageing. These results reveal ER-phagy and ER dynamics as pronounced, underappreciated mechanisms of both normal ageing and age-delaying interventions.

DOI: 10.1038/s41556-025-01860-1

Source: https://www.nature.com/articles/s41556-025-01860-1