Hypothesis

Age‑dependent loss of ileal ASBT drives systemic taurine depletion and hepatic ferroptosis through impaired FXR‑FGF19 signaling.

Mechanistic premise

• ASBT mediates reabsorption of taurine‑conjugated bile acids (TBA) in the distal ileum.
• With aging, ASBT expression/activity falls (to be tested), reducing enterohepatic return of TBA.
• Lower luminal TBA diminishes activation of intestinal FXR → ↓ FGF19 secretion → loss of hepatic CYP7A1 repression.
• Unchecked hepatic bile acid synthesis raises intracellular BA load, promoting mitochondrial ROS, lipid peroxidation and ferroptosis susceptibility.
• Simultaneously, reduced TBA reabsorption lowers circulating taurine, a known regulator of mitochondrial complex I activity and glutathione synthesis, further sensitizing hepatocytes to ferroptotic injury.

Testable predictions

1. Expression/Function – Ileal ASBT mRNA and protein will be significantly lower in 24‑month‑old mice vs 3‑month‑old mice; everted gut sac uptake of radiolabeled taurocholate will drop by ≥40%.
2. Systemic taurine – Serum taurine concentrations will correlate positively with ileal ASBT levels (r > 0.6) and inversely with hepatic lipid‑peroxidation (MDA) and ferroptosis markers (ACSL4, PTGS2).
3. Downstream signaling – Ileal FXR target genes (Fgf15, Shp) will be downregulated; portal FGF19 levels will drop; hepatic Cyp7a1 and Cyp8b1 will be up‑regulated.
4. Physiological read‑outs – Animals with reduced ASBT will show impaired glucose tolerance (higher AUC‑GTT) and increased frailty index; these will worsen with age.
5. Intervention specificity – Ileal‑restricted ASBT overexpression (AAV‑villin‑ASBT) or intestinal FXR agonist (fexaramine) in aged mice will restore serum taurine, lower hepatic BA synthesis, reduce ferroptosis biomarkers, and improve glucose tolerance to a greater extent than hepatocyte‑specific ferroptosis inhibition (liproxstatin‑1).

Falsifiability

If any of the following are observed, the hypothesis is refuted:

• No age‑related decline in ileal ASBT expression or transport activity.
• Serum taurine levels remain unchanged despite ASBT loss.
• Hepatic ferroptosis markers do not rise when ASBT is knocked down in young mice.
• Ileal FXR/FGF19 signaling is unaffected by altered bile acid reabsorption.

Broader implication

This positions the ileal bile acid transporter as an upstream gatekeeper of metabolic aging, shifting focus from hepatocyte‑centric ferroptosis to gut‑liver axis therapeutics.

References

[1] https://pmc.ncbi.nlm.nih.gov/articles/PMC12810195/ [2] https://pmc.ncbi.nlm.nih.gov/articles/PMC12549258/ [3] https://doi.org/10.1126/science.abn9257