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<p>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 <i>FXR</i> knockout (<i>FXR</i><sup>−/−</sup>) 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.</p> Graphical abstract <p></p>

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Farnesoid X receptor deficiency accelerates aging and systemic functional decline in male mice

  • 期刊论文

  • 发表日期：

    2026年4月1日

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  • Jing Yu,
  • Bingbing Fan,
  • Hang Shi,
  • Xiaoyan Gao,
  • Lijun Zhang,
  • Wenlong Nie,
  • Yao Fan,
  • Shishuo Wang,
  • Cheng Huang,
  • Shengjie Fan

摘要

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.

Graphical abstract