Hypothesis

Age‑related decline in ileal apical sodium‑dependent bile acid transporter (ASBT) activity precedes hepatic metabolic dysfunction and directly contributes to systemic aging by reducing fibroblast growth factor 19 (FGF19) secretion, thereby impairing bile acid‑mediated glucose homeostasis independently of liver volume or autophagic capacity.

Mechanistic Basis

Aging elevates Src family kinase (SFK) activity in enterocytes, increasing tyrosine phosphorylation of ASBT (SLC10A2). Phosphorylated ASBT is recognized by ubiquitin ligases and targeted for lysosomal degradation, a process exacerbated by age‑related decline in chaperone‑mediated autophagy that normally rescues misfolded transporters. Consequently, ASBT surface density and Vmax for taurocholate uptake fall, decreasing ileal bile acid reabsorption. Reduced intracellular bile acids diminish FXR activation in enterocytes, lowering FGF19 transcription and secretion. Low circulating FGF19 fails to activate hepatic FGFR4/β‑Klotho signaling, blunting the FGF19‑mediated suppression of gluconeogenesis and enhancement of glycogen synthesis, thus promoting hepatic insulin resistance and systemic metabolic aging.

Predictions and Experimental Design

1. Transport kinetics – Na⁺‑dependent taurocholate uptake in ileal brush border vesicles will show a significant reduction in Vmax (≈30‑40%) in 24‑month‑old mice versus 3‑month‑old controls, while Km remains unchanged.
2. Signaling read‑outs – Plasma FGF19 levels will be proportionally lower in aged mice, correlating inversely with hepatic phospho‑ERK1/2 (FGFR4 downstream) and positively with fasting glucose and insulin tolerance test AUC.
3. Mechanistic linkage – Pharmacologic inhibition of SFK (e.g., PP2) or genetic upregulation of autophagy (e.g., intestinal‑specific Atg7 overexpression) in aged mice will restore ASBT Vmax, normalize FGF19, and improve glucose tolerance without altering liver mass or hepatic autophagy markers.
4. Human relevance – In a cross‑sectional human cohort, intestinal ASBT mRNA expression (from mucosal biopsies) will decline with age and predict lower serum FGF19 and higher HOMA‑IR after adjusting for hepatic steatosis and ALT.

Experimental groups: young control, aged control, aged+SFK inhibitor, aged+autophagy enhancer, aged+vehicle. Outcomes measured at 4‑week intervals: ileal vesicle transport assay, Western blot for phospho‑ASBT (Tyr), lysosomal markers (LAMP1), FGF19 ELISA, hepatic p‑ERK, glucose tolerance, insulin tolerance, and indirect calorimetry.

Potential Outcomes

• Confirmation – If aged mice exhibit reduced ASBT Vmax, elevated phospho‑ASBT, lysosomal accumulation, low FGF19, and metabolic impairment that is rescued by SFK inhibition or autophagy boost, the hypothesis is supported.
• Refutation – If ASBT transport remains unchanged with age, or if manipulating SFK/autophagy fails to alter FGF19 or metabolic parameters despite restoring ASBT levels, then ileal ASBT senescence is not a primary driver of systemic metabolic aging, redirecting focus to hepatic or extraintestinal mechanisms.

This framework provides a clear, falsifiable pathway linking intestinal transporter senescence to endocrine bile acid signaling and organismal metabolic decline, offering a testable target for interventions aimed at extending metabolic healthspan.