Hypothesis

Aging‑induced intestinal epithelial senescence secretes a glucocorticoid‑rich SASP that directly upregulates ileal ASBT (SLC10A2) via SGK1, creating a feed‑forward loop that traps conjugated primary bile acids in the enterohepatic circulation, elevates serum and brain bile acid levels, and drives cognitive impairment.

Mechanistic Rationale

1. Senescence‑derived glucocorticoids – Senescent intestinal epithelial cells increase local cortisol/corticosteroid production (or activate glucocorticoid receptor signaling) as part of the SASP, mirroring the hepatic steatosis model where senescence‑SASP drives metabolic dysfunction 4.
2. SGK1 activation – Glucocorticoid‑bound receptor induces SGK1 transcription, which phosphorylates and stabilizes ASBT at the apical membrane, enhancing reabsorption of conjugated primary bile acids (CPBAs) 1.
3. Disrupted FXR‑FGF15 feedback – Age‑related dysbiosis reduces bile‑salt‑hydrolase activity, preserving CPBAs in the lumen and sustaining FXR activation; however, the heightened ASBT activity overwhelms the feedback, leading to net hepatic BA synthesis suppression (CYP7A1 down) 1 3.
4. Spillover to circulation – Excess CPBA reabsorption raises portal and systemic bile acid concentrations, facilitating blood‑brain barrier transport and accumulation in hippocampal neurons, where they perturb synaptic plasticity and promote synapse loss 2.
5. Dynamic transport deficit – Ex vivo uptake assays reveal that despite higher serum CPBAs, luminal CPBAs fall faster because ASBT is hyper‑active, a phenotype invisible to static plasma panels 1; this mismatch serves as an early biomarker of intestinal senescence.

Testable Predictions

• Prediction 1: Pharmacological clearance of senescent intestinal epithelial cells (using a senolytic such as dasatinib + quercetin) will reduce ileal SGK1 and ASBT expression, lower serum CPBA levels, and rescue cognitive deficits in aged mice.
• Prediction 2: Aged mice lacking glucocorticoid receptor specifically in intestinal epithelium (Villin‑Cre;GR^fl/fl) will show blunted ASBT upregulation despite senescence, normal CPBA reabsorption, and preserved cognition.
• Prediction 3: Dynamic ileal uptake assays in middle‑aged humans will predict future cognitive decline better than fasting serum bile acid concentrations.

Experimental Approach

• Mouse models: Induce intestinal senescence via low‑dose irradiation or p16‑INK‑CRE‑driven dCas9‑KRAB; treat with senolytics or intestinal‑specific GR knockout; measure SGK1, ASBT (qPCR, Western), CPBA uptake in everted gut sacs, serum/brain BA LC‑MS, and cognition (Morris water maze).
• Human pilot: Recruit volunteers aged 55‑80; obtain ileal biopsies via colonoscopy; assay senescence markers (p16, SASP cytokines), SGK1, ASBT; perform ex vivo uptake of taurocholate; follow serum BA and cognitive testing over 2 years.

If senescence drives ASBT via glucocorticoid‑SGK1, intervening at the senescence‑SASP level should break the bile‑acid‑cognition axis, offering a mechanistic alternative to liver‑centric models of metabolic aging.