Hypothesis

Age‑associated decline in circulating taurine reduces the pool of taurine‑conjugated bile acids, impairing ASBT‑mediated reabsorption in the terminal ileum and initiating a cascade that destabilizes enterohepatic circulation, promotes hepatic senescence, and accelerates metabolic aging.

Mechanistic Insight

Taurine is not only a bile acid conjugate; it also stabilizes mitochondrial membranes and modulates intracellular calcium in enterocytes. With aging, taurine deficiency circulating taurine levels decline significantly with aging leads to two convergent hits on ileal function:

1. Reduced ligand availability – ASBT exhibits higher affinity for taurine‑conjugated over unconjugated bile acids ASBT preferentially transports conjugated over unconjugated bile acids. Lower taurine shifts the bile acid pool toward glycine‑conjugated and unconjugated species, decreasing ASBT transport velocity (Vmax) and increasing Km.
2. Enterocyte bioenergetic failure – Taurine loss compromises mitochondrial respiration and increases ROS production in ileal epithelial cells (see mitochondrial role of taurine in aging literature). This triggers AMPK inhibition and mTORC1 activation, suppressing autophagy and promoting a senescent phenotype characterized by p16^INK4a^ upregulation and SASP secretion.

The combined effect diminishes bile acid reclamation, raising fecal bile acid loss. Hepatic compensatory upregulation of CYP7A1 and LDL‑R disrupting ASBT function upregulates hepatic cholesterol 7α‑hydroxylase and LDL receptors attempts to maintain bile acid pool size, but chronic overexpression drives cholesterol overload, ER stress, and ferroptosis susceptibility in hepatocytes aging liver showing ferroptosis, SIRT1 decline, and MASLD vulnerability. Thus, ileal ASBT dysfunction acts as an upstream trigger that converts liver‑centric aging pathways into a systemic metabolic syndrome.

Testable Predictions

| Prediction | Experimental Approach | Expected Outcome if Hypothesis True | Falsifying Outcome | |------------|----------------------|-------------------------------------|--------------------| | ASBT expression and uptake kinetics decline with age in mouse ileum | Quantify Asbt mRNA, protein, and [^3H]‑taurocholate uptake in young (3 mo) vs aged (24 mo) mice; repeat with taurine supplementation (2 % w/w in diet) | Aged mice show ↓ Asbt protein (~40 %), ↓ Vmax, ↑ Km; taurine rescue restores values to young levels | No age‑related change or taurine fails to improve ASBT parameters | | Fecal bile acid excretion rises with age and correlates with circulating taurine | Measure total bile acids in feces via LC‑MS; correlate with plasma taurine circulating taurine levels decline significantly with aging | Aged mice exhibit 2‑3× higher fecal bile acids; inverse correlation (r < ‑0.6) with taurine | No increase or no correlation | | Hepatic senescence markers increase secondary to ileal ASBT loss | Assess hepatic p21^Cip1^, p16^INK4a^, SASP cytokines, and ferroptosis markers (ACSL4, lipid ROS) in aged vs young; test whether ileal‑specific Asbt overexpression prevents these changes | Aged livers show ↑ senescence/ferroptosis; ileal Asbt overexpression normalizes markers despite systemic taurine low | Hepatic markers unchanged by ileal Asbt manipulation | | Taurine supplementation ameliorates age‑related metabolic dysfunction | Long‑term taurine diet in aged mice; monitor glucose tolerance, LDL‑C, liver histology (fibrosis, MASLD) | Improved glucose tolerance, ↓ LDL‑C, reduced fibrosis scores vs control | No metabolic benefit |

These predictions are directly falsifiable: failure of any key prediction (e.g., taurine does not rescue ASBT function or hepatic senescence) would require revising the model, whereas concordance across multiple levels would support the hypothesis that ileal ASBT decline, driven by taurine depletion, is an early driver of hepatic aging and systemic metabolic decline.