Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 35, Pages 17383-17392Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1900055116
Keywords
endoplasmic reticulum; dietary restriction; hormesis; life span; aging
Categories
Funding
- Department of Biotechnology (DBT), Government of India
- Ramalingaswami Fellowship [BT/HRD/35/02/12/2008]
- National Bioscience Award for Career Development [BT/HRD/NBA/38/04/2016]
- Department of Science and Technology (DST)-Science and Engineering Research Board (SERB) [EMR/2014/000377]
- National Institute of Immunology
- Swarnajayanti Fellowship from DST-SERB [DST/SJF/LSA-01/2015-16]
- Council of Scientific and Industrial Research (CSIR)
- DBT-JRF
- NIH Office of Research Infrastructure Programs [P40 OD010440]
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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.
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