Department of Biochemistry, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, 31096, Israel.
Department of Biochemistry, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, 31096, Israel.
Exp Cell Res. 2021 Feb 15;399(2):112474. doi: 10.1016/j.yexcr.2021.112474. Epub 2021 Jan 9.
The aging proteostasis decline manifests in a failure of aging cells and organisms to properly respond to proteotoxic challenges. This proteostasis collapse has long been considered a hallmark of aging in nematodes, and has recently been shown to occur also in human cells upon entry to senescence, opening the way to exploring the phenomenon in the broader context of human aging. Cellular senescence is part of the normal human physiology of aging, with senescent cell accumulation as a prominent feature of aged tissues. Being highly resistant to cell death, senescent cells, as they accumulate, become pro-inflammatory and promote disease. Here we discuss the causes of human senescence proteostasis decline, in view of the current literature on nematodes, on the one hand, and senescence, on the other hand. We review two major aspects of the phenomenon: (1) the decline in transcriptional activation of stress-response pathways, and (2) impairments in proteasome function. We further outline potential underlying mechanisms of transcriptional proteostasis decline, focusing on reduced chromatin dynamics and compromised nuclear integrity. Finally, we discuss potential strategies for reinforcing proteostasis as a means to improve organismal health and address the relationship to senolytics.
衰老的蛋白质稳态下降表现为衰老细胞和生物体无法正常应对蛋白质毒性挑战。这种蛋白质稳态崩溃长期以来一直被认为是线虫衰老的标志，最近也被证明在人类细胞进入衰老时也会发生，为在更广泛的人类衰老背景下探索这一现象开辟了道路。细胞衰老 是人类衰老生理过程的一部分，衰老细胞的积累是老年组织的一个突出特征。衰老细胞对细胞死亡有很高的抵抗力，随着它们的积累，会变得具有炎症性并促进疾病。在这里，我们一方面从线虫的现有文献，另一方面从衰老的角度讨论人类衰老时蛋白质稳态下降的原因。我们综述了这一现象的两个主要方面：(1) 应激反应途径转录激活的下降，和 (2) 蛋白酶体功能的损伤。我们进一步概述了转录蛋白质稳态下降的潜在机制，重点关注染色质动力学降低和核完整性受损。最后，我们讨论了加强蛋白质稳态作为改善机体健康和解决与衰老相关的策略。
