Core Hypothesis

A progressive decline in ileal apical sodium‑dependent bile acid transporter (ASBT, SLC10A2) expression with age reduces reabsorption of taurine‑conjugated bile acids, increasing fecal loss of taurine and depleting hepatic taurine pools. This taurine deficit diminishes mitochondrial antioxidant capacity and impairs FXR‑dependent repression of inflammatory pathways, thereby linking intestinal transporter aging to systemic inflammaging.

Mechanistic Rationale

• ASBT mediates ileal uptake of tauro‑ and tauro‑ursodeoxycholic acids [https://doi.org/10.1101/2025.06.19.660551]; loss of this transporter shifts the bile acid pool toward non‑taurine species, raising luminal deconjugation by gut microbes and elevating secondary bile acids that activate TGR5‑driven cytokine release.
• Taurine is a critical mitochondrial buffer that scavenges hypochlorous acid and supports electron transport chain efficiency [https://www.science.org/doi/epdf/10.1126/science.abn9257]; its systemic decline with age reduces hepatic ATP production and increases ROS, sensitizing hepatocytes to senescence‑associated secretory phenotype (SASP).
• FXR signaling depends on intracellular bile acid levels; reduced ileal ASBT lowers portal bile acid return, weakening FXR activation and its anti‑inflammatory SHP‑NFκB axis, a shift observed in cholestasis where ASBT is suppressed [https://pmc.ncbi.nlm.nih.gov/articles/PMC1856080/].
• Intestinal barrier integrity relies on taurine‑mediated mucus stabilization; loss of luminal taurine compromises goblet cell secretion, facilitating LPS translocation and hepatic inflammation [https://pmc.ncbi.nlm.nih.gov/articles/PMC12261135/][https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.660179/full].

Testable Predictions

1. Expression & Function – Aged mice (24 mo) will show ≥40 % reduction in ileal ASBT mRNA, protein, and uptake of radiolabeled TCDCA compared with young (3 mo) controls; SeHCAT retention will be lower, reflecting diminished reabsorptive capacity [https://pmc.ncbi.nlm.nih.gov/articles/PMC1856080/].
2. Taurine Flux – Fecal taurine‑conjugated bile acid excretion will be twice as high in aged animals, correlating inversely with serum and hepatic taurine concentrations (rho ≈ ‑0.7) [https://www.science.org/doi/epdf/10.1126/science.abn9257].
3. Rescue Experiments – ileal‑specific ASBT overexpression in aged mice will restore fecal bile acid reabsorption, elevate hepatic taurine by ~30 %, decrease hepatic ROS, and attenuate SASP markers (IL‑6, CCL2). Conversely, pharmacologic ASBT inhibition in young mice will recapitulate the aged taurine loss phenotype.
4. Human Translation – Cross‑sectional analysis of duodenal biopsies from younger (<35 yr) vs older (>65 yr) donors will reveal reduced ASBT immunoreactivity; serum taurine levels will positively correlate with ASBT scores after adjusting for BMI and renal function.

Falsifiability

If aged individuals exhibit no significant decline in ileal ASBT expression or function, or if fecal taurine‑conjugated bile acid excretion does not rise with age despite measurable systemic taurine depletion, the hypothesis is refuted. Likewise, if restoring ASBT fails to improve hepatic taurine or inflammaging markers, the proposed mechanistic link is invalid.

Broader Implications

Establishing ASBT as a molecular checkpoint connecting gut bile acid handling to hepatic metabolic resilience would shift focus from liver‑centric bile acid diagnostics to functional intestinal transport assays (e.g., dynamic SeHCAT or PET‑based bile acid tracers) as early biomarkers of aging‑related organ decline.