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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2019-08, Vol.116 (35), p.17383-17392
• Main Authors: Matai, Latika, Sarkar, Gautam Chandra, Chamoli, Manish, Malik, Yasir, Kumar, Shashi Shekhar, Rautela, Umanshi, Jana, Nihar Ranjan, Chakraborty, Kausik, Mukhopadhyay, Arnab
• Format: Article
• Language: English
• Subjects: Age; Age related diseases; Aging; Animals; Biological Sciences; Caenorhabditis elegans - genetics; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Caloric Restriction; Degradation; Dietary restrictions; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum Stress; Gene expression; Homeostasis; Hormesis; Life span; Longevity; Longevity - genetics; Neurodegenerative diseases; Neurological diseases; Pharmacology; PNAS Plus; Polyglutamine; Preconditioning; Protein folding; Proteins; Trinucleotide repeat diseases; Unfolded Protein Response; Viability
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1900055116

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 age-related 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.