Hypothesis

With advancing age, ileal apical sodium-dependent bile acid transporter (ASBT) function declines beyond what is predicted by reduced expression alone, leading to altered bile acid reabsorption, diminished intestinal FXR activation, and reduced FGF19 secretion. This intestinal-hepatic signaling deficit shifts hepatic bile acid synthesis toward a more hydrophilic, taurine‑depleted pool, exacerbating mitochondrial dysfunction and promoting systemic metabolic senescence.

Mechanistic Basis

• ASBT exhibits 3‑5 fold higher affinity for taurine‑conjugated bile acids; age‑related taurine depletion reduces substrate availability, compounding transporter downregulation (science.org/doi/epdf/10.1126/science.abn9257).
• Dynamic uptake assays show that Vmax and Km changes better predict mortality than static serum bile acid levels (PMC4899173).
• Reduced intestinal FXR signaling lowers FGF19 release, removing a key negative feedback on hepatic CYP7A1, thereby altering bile acid pool composition and hepatic metabolism (PMC3047154).
• Exosome‑mediated transfer of miR‑192 from ileal enterocytes to hepatocytes, known to modulate FXR activity, may also be disrupted with age, further uncoupling intestinal‑hepatic crosstalk.

Predictions

1. In humans, ileal ASBT Vmax will decrease 30‑50 % by the seventh decade, while Km for taurocholate will increase, indicating lower affinity independent of expression levels.
2. Serum tauro‑cholate concentrations will fall disproportionately to total bile acids, correlating with reduced intestinal FXR target gene expression (e.g., FGF19) in circulating exosomes.
3. Older subjects will exhibit a higher ratio of hydrophilic (β‑muricholic, ursodeoxycholic) to hydrophobic (cholic, deoxycholic) bile acids, reflecting impaired hepatic feedback.
4. Supplementation with taurocholate or taurine in aged mice will restore ileal ASBT Vmax, normalize serum FGF19, and improve glucose tolerance and mitochondrial respiration.

Experimental Design

• Human cohort: Obtain ileal biopsies from participants aged 20‑80 years (n = 6 per decade). Measure ASBT protein (Western blot), mRNA (qPCR), and perform ex vivo uptake assays with [³H]‑taurocholate to derive Vmax and Km. Simultaneously collect serum for bile acid profiling (LC‑MS), FGF19, and exosomal miR‑192.
• Animal validation: Use 24‑month‑old C57BL/6 mice. Treat subgroups with oral taurocholate (0.5 % w/v) or taurine (1 % in drinking water) for 8 weeks. Controls receive vehicle. Assess ileal ASBT kinetics, hepatic CYP7A1 expression, serum FGF19, glucose tolerance test, and mitochondrial respiration in liver and muscle.
• Intervention specificity: Include a group receiving ASBT‑specific inhibitor (e.g., volixibat) to confirm that observed effects are transporter‑dependent.

Potential Outcomes

• Confirmation of age‑related kinetic defects would refute the notion that transporter loss is purely transcriptional, establishing a functional biomarker of intestinal aging.
• Rescue by taurocholate/taurine would support a dual‑hit model where substrate limitation amplifies transporter decline, offering a therapeutic avenue targeting the intestinal node of enterohepatic circulation.
• Failure to observe changes would necessitate re‑evaluation of hepatic‑centric models and push focus toward alternative pathways (e.g., microbiota‑mediated bile acid transformation).

This framework generates falsifiable, quantitative predictions that can be addressed with currently available techniques, directly addressing the highlighted gap in dynamic ileal transport research during aging.