The functional health of the proteome is determined by properties of the proteostasis network (PN) that regulates protein synthesis, folding, macromolecular assembly, translocation, and degradation. In eukaryotes, the PN also integrates protein biogenesis across compartments within the cell and between tissues of metazoans for organismal health and longevity. Additionally, in metazoans, proteome stability and the functional health of proteins is optimized for development and yet declines throughout aging, accelerating the risk for misfolding, aggregation, and cellular dysfunction. Here, I describe the cell-nonautonomous regulation of organismal PN by tissue communication and cell stress-response pathways. These systems are robust from development through reproductive maturity and are genetically programmed to decline abruptly in early adulthood by repression of the heat shock response and other cell-protective stress responses, thus compromising the ability of cells and tissues to properly buffer against the cumulative stress of protein damage during aging. While the failure of multiple protein quality control processes during aging challenges cellular function and tissue health, genetic studies, and the identification of small-molecule proteostasis regulators suggests strategies that can be employed to reset the PN with potential benefit on cellular health and organismal longevity.

中文翻译：

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衰老和疾病中蛋白质稳态的细胞非自主调节。

蛋白质组的功能健康由调节蛋白质合成、折叠、大分子组装、易位和降解的蛋白质稳态网络 (PN) 的特性决定。在真核生物中，PN 还整合了跨细胞内隔室和后生动物组织之间的蛋白质生物发生，以促进机体健康和长寿。此外，在后生动物中，蛋白质组稳定性和蛋白质的功能健康针对发育进行了优化，但在整个衰老过程中都会下降，从而加速了错误折叠、聚集和细胞功能障碍的风险。在这里，我描述了通过组织通讯和细胞应激反应途径对有机体 PN 进行的细胞非自主调节。这些系统从发育到生殖成熟都很健壮，并且通过基因编程在成年早期通过抑制热休克反应和其他细胞保护性应激反应突然下降，从而损害细胞和组织适当缓冲累积应激的能力。衰老过程中的蛋白质损伤。虽然衰老过程中多种蛋白质质量控​​制过程的失败对细胞功能和组织健康提出了挑战，但基因研究和小分子蛋白质稳态调节剂的鉴定表明，可用于重置 PN 的策略可能对细胞健康和机体寿命有益。从而损害细胞和组织在衰老过程中适当缓冲蛋白质损伤累积压力的能力。虽然衰老过程中多种蛋白质质量控​​制过程的失败对细胞功能和组织健康提出了挑战，但基因研究和小分子蛋白质稳态调节剂的鉴定表明，可用于重置 PN 的策略可能对细胞健康和机体寿命有益。从而损害细胞和组织在衰老过程中适当缓冲蛋白质损伤累积压力的能力。虽然衰老过程中多种蛋白质质量控​​制过程的失败对细胞功能和组织健康提出了挑战，但基因研究和小分子蛋白质稳态调节剂的鉴定表明，可用于重置 PN 的策略可能对细胞健康和机体寿命有益。