Hypothesis

Age‑related decline in ileal apical sodium‑dependent bile acid transporter (ASBT/SLC10A2) function is not a passive consequence of reduced enterocyte turnover but is actively driven by the senescence‑associated secretory phenotype (SASP) that suppresses ASBT transcription via NF‑κB signaling, an effect amplified by age‑linked taurine scarcity that shifts the bile acid pool toward glycine‑conjugated species with lower ASBT affinity.

Mechanistic Rationale

1. SASP‑mediated transcriptional repression – Cellular senescence in the intestinal epithelium increases secretion of IL‑6, IL‑1β, and TNF‑α, which activate NF‑κB in neighboring enterocytes. NF‑κB binding to the ASBT promoter has been shown to repress transcription in inflammatory bowel disease models (4). We predict that analogous NF‑κB activation occurs during inflammaging, directly lowering ASBT mRNA and protein levels.
2. Taurine dependence of ASBT kinetics – ASBT transports taurine‑conjugated bile acids (T‑BAs) with higher Vmax than glycine‑conjugated BAs (6). Age‑related decline in circulating taurine (5) reduces the proportion of T‑BAs in the enterohepatic pool, forcing reliance on slower glycine‑BA transport and further decreasing net bile acid reabsorption.
3. Feedback onto hepatic synthesis – Reduced ileal BA uptake diminishes FGF15/19 secretion, lifting hepatic FXR‑mediated repression of CYP7A1 and increasing de novo BA synthesis. This creates a futile cycle: heightened hepatic BA production coupled with impaired intestinal retrieval elevates circulating BA concentrations, potentially contributing to metabolic inflammation and insulin resistance observed in aging.

Testable Predictions

• Prediction 1: Intestinal epithelial cells isolated from aged mice (≥24 mo) will show lower ASBT protein abundance and reduced uptake of taurocholate compared with young counterparts (3 mo), correlating with increased SASP marker (p16^INK4a^, SA‑β‑gal) expression and NF‑κB nuclear localization.
• Prediction 2: Pharmacological inhibition of NF‑κB (e.g., with Bay 11‑7082) or genetic ablation of p16^INK4a^‑positive senescent cells (via senolytic treatment) in aged mice will restore ASBT expression and taurocholate transport rates to youthful levels.
• Prediction 3: Dietary taurine supplementation (1 % w/w) in aged mice will increase the proportion of taurine‑conjugated BAs in the luminal pool and partially rescue ASBT‑mediated uptake, even without altering senescence burden.
• Prediction 4: Organoid cultures derived from human colonic biopsies stratified by age will recapitulate the inverse correlation between SASP cytokine secretion (IL‑6, TNF‑α) and ASBT transport activity, which can be reversed by taurine addition.

Experimental Approach

1. Mouse models – Compare young (3 mo) and aged (24 mo) C57BL/6J mice; treat subsets with senolytic (dasatinib + quercetin) or NF‑κB inhibitor for 2 weeks; measure ileal ASBT mRNA/protein (qPCR, Western), transport of radiolabeled taurocholate vs glycocholate in everted gut sacks, plasma BA composition (LC‑MS), and FGF19 levels.
2. Taurine manipulation – Provide aged mice with taurine‑supplemented water (2 % w/v) for 4 weeks; assess whether BA conjugation shifts toward T‑BAs and whether ASBT function improves independently of senescence markers.
3. Human validation – Obtain ileal biopsies (via colonoscopy with terminal ileum intubation) from volunteers aged 20‑35 y and 65‑75 y; quantify SASP cytokines in biopsy supernatant, ASBT immunofluorescence, and ex vivo uptake of fluorescently labeled taurocholate.
4. Rescue experiments – Transfect aged mouse ileal organoids with NF‑κB‑repressing IκBα super‑repressor or treat with taurine; evaluate ASBT expression and transport.

Falsifiability

If aged animals exhibit no reduction in ASBT‑mediated taurocholate uptake, no increase in SASP/NF‑κB activity, or no improvement with senolytics/NF‑κB blockade or taurine supplementation, the hypothesis would be refuted. Conversely, confirmation of any of the above predictions would support the mechanistic link between inflammaging, taurine deficiency, and ileal ASBT decline, shifting focus from hepatic‑centric views to intestinal transporter regulation in metabolic aging.