Intestinal pooling of taurine conjugated bile acids is associated with tissue aging and senescent immune evasion.

Background: Aging drives metabolic decline and the accumulation of senescent cells that evade immune clearance. The mechanisms linking host-microbiome co-metabolism to peripheral tissue deterioration remain unclear. We hypothesized that age-dysregulated enterohepatic bile acid (BA) signaling directly promotes systemic aging and immune senescence. Methods: We conducted targeted BA metabolomics in the intestinal and peripheral compartments of young and middle-aged mice. To establish causality, 12-month-old mice underwent systemic BA depletion via a cholestyramine diet, followed by assessments of Farnesoid X Receptor (FXR) and Retinoic Acid Receptor alpha (RARα) signaling, cellular senescence, PD-L1/PD-L2 expression, and multi-organ transcriptomics. Results: Advancing age sequesters potent endogenous FXR antagonists (T-α-MCA, T-ω-MCA) within the gut lumen. However, peripheral tissues (lungs, skin, lymph nodes) progressively decrease in the levels of these regulatory molecules. This spatial disconnect triggers chronic peripheral FXR hyperactivation, disrupting local RARα signaling. which accelerates the accumulation of senescent cells and actively shields them from immune clearance by upregulating PD-L1 and PD-L2 surface checkpoints. Crucially, systemic BA sequestration reversed this phenotype. Depleting the pathological BA pool suppressed peripheral FXR overreaction. Further cleared the senescent burden, stripped senescent cells of their immune-evasive checkpoints, and drove a multi-organ of age-associated transcriptional changes. Conclusion: The age-altered BA metabolome may contribute to systemic aging and to upregulation of PD-L1 and PD-L2. Rebalancing the enterohepatic BA network to relieve peripheral FXR hyperactivation represents a potent, broad-spectrum geroprotective strategy to restore immune surveillance and multi-organ homeostasis.