文章基本信息

标题：Dietary restriction improves proteostasis and increases life span through endoplasmic reticulum hormesis
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作者：Latika Matai ; Gautam Chandra Sarkar ; Manish Chamoli 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2019
卷号：116
期号：35
页码：17383-17392
DOI：10.1073/pnas.1900055116
出版社：The National Academy of Sciences of the United States of America
摘要：Unfolded protein response (UPR) of the endoplasmic reticulum (UPR^ER) helps maintain proteostasis in the cell. The ability to mount an effective UPR^ER to external stress (iUPR^ER) decreases with age and is linked to the pathophysiology of multiple age-related disorders. Here, we show that a transient pharmacological ER stress, imposed early in development on Caenorhabditis elegans , enhances proteostasis, prevents iUPR^ER decline with age, and increases adult life span. Importantly, dietary restriction (DR), that has a conserved positive effect on life span, employs this mechanism of ER hormesis for longevity assurance. We found that only the IRE-1–XBP-1 branch of UPR^ER is required for the longevity effects, resulting in increased ER-associated degradation (ERAD) gene expression and degradation of ER resident proteins during DR. Further, both ER hormesis and DR protect against polyglutamine aggregation in an IRE-1–dependent manner. We show that the DR-specific FOXA transcription factor PHA-4 transcriptionally regulates the genes required for ER homeostasis and is required for ER preconditioning-induced life span extension. Finally, we show that ER hormesis improves proteostasis and viability in a mammalian cellular model of neurodegenerative disease. Together, our study identifies a mechanism by which DR offers its benefits and opens the possibility of using ER-targeted pharmacological interventions to mimic the prolongevity effects of DR.
关键词：endoplasmic reticulum ; dietary restriction ; hormesis ; life span ; aging