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

Research output: Contribution to journalArticle

27 Downloads (Pure)

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

Fingerprint

Hormesis
Endoplasmic Reticulum
Pharmacology
Unfolded Protein Response
Dietary Proteins
Caenorhabditis elegans
Life Expectancy
Neurodegenerative Diseases
Homeostasis
Transcription Factors
Gene Expression
Genes

Keywords

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

Cite this

Matai, Latika ; Sarkar, Gautam Chandra ; Chamoli, Manish ; Malik, Yasir ; Kumar, Shashi Shekhar ; Rautela, Umanshi ; Jana, Nihar Ranjan ; Chakraborty, Kausik ; Mukhopadhyay, Arnab. / Dietary restriction improves proteostasis and increases life span through endoplasmic reticulum hormesis. In: Proceedings of the National Academy of Sciences of the United States of America. 2019 ; Vol. 116, No. 35. pp. 17383-17392.
@article{0939c163a92b4ffd8d43cbaedae3a8f7,
title = "Dietary restriction improves proteostasis and increases life span through endoplasmic reticulum hormesis",
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.",
keywords = "Aging, Dietary restriction, Endoplasmic reticulum, Hormesis, Life span",
author = "Latika Matai and Sarkar, {Gautam Chandra} and Manish Chamoli and Yasir Malik and Kumar, {Shashi Shekhar} and Umanshi Rautela and Jana, {Nihar Ranjan} and Kausik Chakraborty and Arnab Mukhopadhyay",
year = "2019",
month = "8",
day = "27",
doi = "10.1073/pnas.1900055116",
language = "English",
volume = "116",
pages = "17383--17392",
journal = "Proceedings of the National Academy of Sciences",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "35",

}

Dietary restriction improves proteostasis and increases life span through endoplasmic reticulum hormesis. / Matai, Latika; Sarkar, Gautam Chandra; Chamoli, Manish; Malik, Yasir; Kumar, Shashi Shekhar; Rautela, Umanshi; Jana, Nihar Ranjan; Chakraborty, Kausik; Mukhopadhyay, Arnab.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 35, 27.08.2019, p. 17383-17392.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Dietary restriction improves proteostasis and increases life span through endoplasmic reticulum hormesis

AU - Matai, Latika

AU - Sarkar, Gautam Chandra

AU - Chamoli, Manish

AU - Malik, Yasir

AU - Kumar, Shashi Shekhar

AU - Rautela, Umanshi

AU - Jana, Nihar Ranjan

AU - Chakraborty, Kausik

AU - Mukhopadhyay, Arnab

PY - 2019/8/27

Y1 - 2019/8/27

N2 - 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.

AB - 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.

KW - Aging

KW - Dietary restriction

KW - Endoplasmic reticulum

KW - Hormesis

KW - Life span

UR - http://www.scopus.com/inward/record.url?scp=85071487556&partnerID=8YFLogxK

U2 - 10.1073/pnas.1900055116

DO - 10.1073/pnas.1900055116

M3 - Article

C2 - 31413197

AN - SCOPUS:85071487556

VL - 116

SP - 17383

EP - 17392

JO - Proceedings of the National Academy of Sciences

JF - Proceedings of the National Academy of Sciences

SN - 0027-8424

IS - 35

ER -