Dietary restriction improves proteostasis and increases life span through endoplasmic reticulum hormesis

Latika Matai, Gautam Chandra Sarkar, Manish Chamoli, Yasir Malik, Shashi Shekhar Kumar, Umanshi Rautela, Nihar Ranjan Jana, Kausik Chakraborty, Arnab Mukhopadhyay

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Abstract

Unfolded protein response (UPR) of the endoplasmic reticulum (UPRER) helps maintain proteostasis in the cell. The ability to mount an effective UPRER to external stress (iUPRER) decreases with age and is linked to the pathophysiology of multiple agerelated disorders. Here, we show that a transient pharmacological ER stress, imposed early in development on Caenorhabditis elegans, enhances proteostasis, prevents iUPRER 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 UPRER 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.

Original languageEnglish
Pages (from-to)17383-17392
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number35
Early online date14 Aug 2019
DOIs
Publication statusPublished - 27 Aug 2019

Keywords

  • Aging
  • Dietary restriction
  • Endoplasmic reticulum
  • Hormesis
  • Life span

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    Matai, L., Sarkar, G. C., Chamoli, M., Malik, Y., Kumar, S. S., Rautela, U., Jana, N. R., Chakraborty, K., & Mukhopadhyay, A. (2019). Dietary restriction improves proteostasis and increases life span through endoplasmic reticulum hormesis. Proceedings of the National Academy of Sciences of the United States of America, 116(35), 17383-17392. https://doi.org/10.1073/pnas.1900055116