Clock mediates liver senescence by controlling ER stress

Area of Science:

• Molecular Biology
• Chronobiology
• Cellular Aging

Background:

• Circadian genes influence cell damage and senescence.
• Endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) impact longevity.
• The interplay between the circadian clock and stress pathways is not fully understood.

Purpose of the Study:

• To elucidate the mechanisms linking the circadian clock to ER stress and ROS.
• To investigate the role of the circadian gene Clock in regulating cellular stress and aging.

Main Methods:

• Analysis of liver tissue from Clock mutant mice.
• Investigating Pdia3 transcription regulation by Clock.
• Using siRNA to ablate Pdia3 and assess cellular responses.

Main Results:

• Clock mutant mice show activated ER stress and ROS with aging phenotypes.
• Clock directly regulates Pdia3 transcription, impaired in Clock mutants.
• Pdia3 ablation exacerbates ER stress, UPR, apoptosis, and ROS, leading to senescence.

Conclusions:

• The circadian gene Clock is a key regulator of ER stress and cellular senescence.
• Clock-mediated Pdia3 expression is crucial for maintaining cellular homeostasis.
• Findings offer insights into clinical strategies for preventing aging.