Hypothesis

Age-related systemic taurine depletion shifts hepatic bile acid conjugation patterns toward glycine-dominant species. This conjugation shift reduces the transport efficiency of the ileal apical sodium-dependent bile acid transporter (ASBT). Taurine-conjugated bile acids exhibit higher aqueous solubility and different ASBT binding kinetics compared to glycine conjugates, so the shift creates a functional decline in enterohepatic circulation efficiency—independent of any age-related decrease in ASBT protein expression or transcript levels. This mechanism likely contributes to the intestinal barrier dysfunction identified as an evolutionarily conserved hallmark of aging, establishing a feedback loop where impaired bile acid reabsorption further compromises barrier integrity.

Mechanistic Rationale

The ASBT operates near its transport maximum in healthy adults, leaving minimal reserve capacity for handling altered substrate profiles. Taurine conjugation confers enhanced amphipathic properties and faster transport kinetics; glycine conjugates, being less polar, may compete less effectively for ASBT binding sites while also exhibiting reduced micellar incorporation efficiency. The age-related taurine decline—roughly 50% in humans by age 80—therefore represents a substrate-level insult to the enterohepatic system that hasn't been functionally characterized before.

Testable Predictions

1. Conjugation profile shift: Elderly subjects (>65 years) will show a significantly higher glycine:taurine bile acid conjugation ratio in both serum and ileal aspirates compared to young adults (18-30 years), after controlling for diet and liver function.

2. Transport efficiency decline: Ex vivo Ussing chamber assays of terminal ileum biopsies will demonstrate reduced taurocholate transport rates (though not necessarily glycocholate rates) in older subjects, correlating inversely with circulating taurine levels.

3. Barrier dysfunction correlation: Subjects with the highest glycine:taurine ratios will exhibit increased intestinal permeability—measured via lactulose:mannitol clearance—and lower serum zonulin-1 levels.

Experimental Design

A cross-sectional study comparing young (n=30) and elderly (n=30) participants would quantify serum taurine via mass spectrometry, fasting and postprandial bile acid conjugation profiles via LC-MS/MS, and intestinal permeability. For mechanistic validation, terminal ileal biopsies obtained during colonoscopy (from subjects undergoing screening) would enable ex vivo [3H]-taurocholate uptake assays to directly measure ASBT functional capacity across ages.

Falsifiability

This hypothesis is falsifiable if: (a) elderly subjects show no shift toward glycine-conjugated bile acids despite documented taurine decline; (b) ASBT transport efficiency remains equivalent across age groups when tested functionally; or (c) barrier integrity shows no correlation with bile acid conjugation patterns. The liver-centric bias in existing aging literature has left this intestinal mechanism largely unexplored, which is a notable gap in the field.