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Updated: May 30, 2025

Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
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Activation of Nuclear Receptor CAR: A Pathway to Delay Aging through Enhanced Capacity for Xenobiotic Resistance

Jing Yu1, Xiaoyan Gao1, Hang Shi1

  • 1School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|January 31, 2025
PubMed

Insights

Activating the constitutive androstane receptor (CAR) extends lifespan and improves healthspan by enhancing the body's resistance to xenobiotics, offering a potential anti-aging strategy.

Area of Science:

  • Aging and Gerontology
  • Molecular Biology
  • Pharmacology

Background:

  • Environmental factors influence aging and age-related diseases.
  • Enhancing xenobiotic resistance is a potential anti-aging strategy.
  • The constitutive androstane receptor (CAR) regulates stress response and metabolism.

Purpose of the Study:

  • To investigate the impact of CAR activation on lifespan and healthspan.
  • To explore the underlying mechanisms of CAR's effects on aging.
  • To assess CAR agonists as a potential anti-aging intervention.

Main Methods:

  • Utilized Caenorhabditis elegans (C. elegans), drug-induced premature aging mice, and senescence accelerated P8 (SAMP8) mice as model organisms.
  • Administered CAR agonists CITCO (human) and TCPOBOP (mouse).
  • Assessed lifespan, healthspan, gene expression (anti-stress, detoxification), environmental resistance, and neurodegeneration.

Main Results:

  • CAR agonists CITCO and TCPOBOP significantly prolonged lifespan and healthspan in model organisms.
  • Longevity effects were diminished in CAR-deficient C. elegans (nhr-8/daf-12 mutant) and CAR knockout mice.
  • CITCO activated anti-stress and detoxification genes, enhanced resistance to environmental adversities, and improved age-related neurodegeneration in C. elegans.

Conclusions:

  • CAR activation extends lifespan and healthspan, potentially through enhanced xenobiotic resistance.
  • CAR agonists represent a promising therapeutic target for aging and age-related diseases.
  • The findings suggest a conserved role for CAR in regulating longevity across species.
Keywords:
age‐related neurodegenerationanti‐agingconstitutive androstane receptor (CAR)environmental stimulusxenobiotic resistance

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