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

Area of Science:

• Cellular Biology
• Aging Research
• Molecular Biology

Background:

• The unfolded protein response (UPR) of the endoplasmic reticulum (UPR^ER) is crucial for maintaining cellular proteostasis.
• Impaired UPR^ER function with age is linked to age-related diseases.
• Dietary restriction (DR) is a conserved intervention that extends lifespan.

Purpose of the Study:

• To investigate if early-life ER stress (ER hormesis) can enhance proteostasis and extend lifespan.
• To elucidate the molecular mechanisms underlying ER hormesis and its connection to dietary restriction.
• To determine the role of the UPR^ER pathway in ER hormesis and DR-induced longevity.

Main Methods:

• Pharmacological induction of ER stress in *Caenorhabditis elegans*.
• Genetic analysis of UPR^ER pathway components (IRE-1, XBP-1).
• Assessment of proteostasis, ER-associated degradation (ERAD), and polyglutamine aggregation.
• Investigation of the role of transcription factor PHA-4 in ER homeostasis.
• Validation in a mammalian cell model of neurodegenerative disease.

Main Results:

• Transient ER stress in early development enhances proteostasis, prevents age-related UPR^ER decline, and increases lifespan in *C. elegans*.
• The IRE-1-XBP-1 branch of UPR^ER is essential for ER hormesis and DR-induced longevity.
• ER hormesis and DR increase ERAD gene expression and protein degradation, and protect against polyglutamine aggregation.
• The FOXA transcription factor PHA-4 is required for ER homeostasis and ER preconditioning-induced lifespan extension.
• ER hormesis improves proteostasis and viability in a mammalian cell model of neurodegenerative disease.

Conclusions:

• ER hormesis is a mechanism that enhances proteostasis and extends lifespan, mimicking some benefits of dietary restriction.
• The IRE-1-XBP-1 pathway and PHA-4 are critical for ER hormesis and DR-mediated longevity.
• Targeting ER pathways pharmacologically offers a potential strategy to promote longevity and combat age-related diseases.