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<p>Aging is a risk factor for the development and progression of metabolic impairments. Dietary protein restriction (DPR) is protective against obesity- and age-related metabolic decline by the induction of the fibroblast growth factor (FGF21), which regulates body weight, lipid handling, and energy expenditure. Likewise, FGF21 is established as an endocrine mediator that responds to multiple nutritional inputs, including carbohydrate overload, protein restriction, prolonged fasting, and excess alcohol intake. Here, we show that long-term protein restriction differentially enriches hepatic transcriptomic pathways, that reprograms and regulates energy production and metabolism. Interestingly, both genotypes revealed to have enriched processes of amino acid metabolism and translation. Comparisons among low protein-fed C57BL/6 and <i>Fgf21</i> knockout mice show inverse enrichment for biological processes of monocarboxylic acid, lipid metabolic processes, with fatty acid metabolic process showing genotype differences in cluster analysis. Exclusively, DPR upregulated hepatic signatures related to ATP synthesis in aged C57BL/6, which were not observed in mice deficient of FGF21 signaling. These data suggest that key long-term metabolic adaptations to protein restriction develop through differential FGF21-dependent and independent pathways, which may contribute to the improved systemic healthspan and lifespan observed with protein-restricted diets.</p><p></p>

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FGF21-dependent and -independent liver transcriptomic adaptations to low-protein feeding during aging

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月31日

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  • Jose A. Godoy-Lugo,
  • Khristina E. Young,
  • Prerana Vaddi,
  • Diana C. Albarado,
  • Christopher D. Morrison,
  • Cristal M. Hill

摘要

Aging is a risk factor for the development and progression of metabolic impairments. Dietary protein restriction (DPR) is protective against obesity- and age-related metabolic decline by the induction of the fibroblast growth factor (FGF21), which regulates body weight, lipid handling, and energy expenditure. Likewise, FGF21 is established as an endocrine mediator that responds to multiple nutritional inputs, including carbohydrate overload, protein restriction, prolonged fasting, and excess alcohol intake. Here, we show that long-term protein restriction differentially enriches hepatic transcriptomic pathways, that reprograms and regulates energy production and metabolism. Interestingly, both genotypes revealed to have enriched processes of amino acid metabolism and translation. Comparisons among low protein-fed C57BL/6 and Fgf21 knockout mice show inverse enrichment for biological processes of monocarboxylic acid, lipid metabolic processes, with fatty acid metabolic process showing genotype differences in cluster analysis. Exclusively, DPR upregulated hepatic signatures related to ATP synthesis in aged C57BL/6, which were not observed in mice deficient of FGF21 signaling. These data suggest that key long-term metabolic adaptations to protein restriction develop through differential FGF21-dependent and independent pathways, which may contribute to the improved systemic healthspan and lifespan observed with protein-restricted diets.