Tryptophan metabolism regulates immunosenescence and inflammaging: The macrophage immunometabolic axis and...

Aging features two linked immune traits: immunosenescence and chronic low-grade inflammaging. Other than senescent lymphocytes, pathologically remodelled macrophages are key drivers of age-related immune dysfunction, mainly via tryptophan (Trp) metabolism through the kynurenine pathway (KP) and microbiota-related indole pathway. This review suggests a bidirectional amplification loop model, in which dysbiosis of the microbiota in the aged gut causes decreased production of microbial indoles and subsequent deficit in aryl hydrocarbon receptor (AhR) signalling in intestinal mucosal macrophages. This causes epithelial barrier dysfunction and translocation of lipopolysaccharide (LPS) which, in the periphery, leads to over-activation of the KP and reprograming of peripheral macrophage populations to a pro-inflammatory M1 phenotype. Systemic KP metabolites are then taken into the gut lumen by enterohepatic circulation and the systemic circulation and interact with indole-derived AhR ligands left over, inducing biased transcriptional profiles that further disrupt macrophage function in the gut and result in a self-sustaining feedback loop. This loop involves the NLRP3 inflammasome as a node point for convergence of inflammatory signals, and CD38 as a pathological ratchet: CD38-mediated NAD⁺ depletion inactivates SIRT1, which removes inhibition of NF-κB and re-induces CD38 to lock reversible M1 polarization in a cell-intrinsic and metabolically locked pro-inflammatory state. We term this state macrophage-specific SASP (mSASP), marked by persistent pro-inflammatory cytokine release and metabolic irreversibility. This macrophage-centred model updates the view of immune aging and highlights gut, AhR, KP and NAD⁺ as promising therapeutic targets for aging. We present this as a hypothesis-generating conceptual framework; although individual components of the model are supported by published evidence, the integrated loop has not been experimentally validated as a whole.