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Updated: Apr 2, 2026
Frailty Assessment in an Aging Mouse Model
Published on: September 23, 2025
Farnesoid X receptor deficiency accelerates aging and systemic functional decline in male mice
Jing Yu1, Bingbing Fan1, Hang Shi1
1School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
Abstract:
Aging is accompanied by progressive functional decline, and nuclear receptors have become significant modulators of the process. Farnesoid X receptor (FXR), a ligand activated nuclear receptor transcription factor that regulates genes involved in bile acid and metabolic homeostasis, has been implicated in aging, yet genetic evidence remains limited. In this study, we demonstrate that FXR knockout (FXR-/-) mice have significantly shorter lifespan and healthspan than WT mice. FXR deficiency led to aggravated neurodegeneration, impaired motor function, multi-organ deterioration, and profound metabolic imbalance. Transcriptomic profiling further revealed a general dysregulation of aging-related pathways, including suppression of p53 signaling, PI3K-Akt signaling, and xenobiotic metabolism, alongside aberrant activation of bile acid and lipid metabolic flux. These results confirm that FXR is an essential regulator of systemic homeostasis and aging, and provide direct genetic evidence that its loss accelerates physiological decline. Our results highlight FXR as a promising therapeutic target for interventions aimed at preserving healthspan and delaying age-related diseases.
Insights
Farnesoid X receptor (FXR) deficiency significantly shortens lifespan and healthspan in mice, accelerating aging and metabolic decline. This study provides genetic evidence that FXR is crucial for maintaining systemic homeostasis and delaying age-related diseases.
Area of Science:
- Gerontology
- Molecular Biology
- Metabolic Homeostasis
Background:
- Aging is characterized by functional decline, with nuclear receptors emerging as key regulators.
- The Farnesoid X receptor (FXR), a nuclear receptor, influences bile acid and metabolic homeostasis.
- Limited genetic evidence exists regarding FXR's role in the aging process.
Purpose of the Study:
- To investigate the genetic impact of FXR deficiency on lifespan and healthspan.
- To elucidate the molecular mechanisms by which FXR influences aging and systemic homeostasis.
Main Methods:
- Utilized FXR knockout (FXR-/-) and wild-type (WT) mice for comparative lifespan and healthspan analysis.
- Conducted transcriptomic profiling to identify dysregulated aging-related pathways.
- Assessed neurodegeneration, motor function, organ health, and metabolic parameters.
Main Results:
- FXR-/- mice exhibited significantly reduced lifespan and healthspan compared to WT mice.
- FXR deficiency resulted in aggravated neurodegeneration, impaired motor function, and multi-organ deterioration.
- Transcriptomic analysis revealed suppressed p53 and PI3K-Akt signaling, impaired xenobiotic metabolism, and dysregulated bile acid/lipid metabolism.
Conclusions:
- FXR is an essential regulator of systemic homeostasis and aging, with its absence accelerating physiological decline.
- Loss of FXR function leads to a pro-aging phenotype, characterized by metabolic and functional impairments.
- FXR represents a potential therapeutic target for interventions aimed at promoting healthy aging and mitigating age-related diseases.
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