Programmatic Adaptive Failure in Myeloid Cells: A Novel Mechanism Linking Frailty to Accelerated Epigenetic Aging

Background Frailty is a hallmark of accelerated biological aging, yet the causal pathways and cellular-molecular mechanisms driving the vicious cycle of "frailty-inflammation-aging" remain unclear. Methods This study employed a multi-level integrative analysis: 1) validation of associations and inflammatory mediation based on the NHANES cohort; 2) establishment of causal chains using two-step Mendelian randomization (including mediation analysis); 3) identification of mechanistic modules through weighted gene co-expression networks and single-cell deconvolution; 4) construction of the AI clinical decision-making system FIRE-AI, integrating inflammatory thresholds, molecular scores, and network pharmacology results. Results Frailty accelerated aging (17.2% mediated by inflammation). Mendelian randomization established the causal chain "frailty → neutrophilia → accelerated aging" (mediation effect 0.309). The BLUE module was found to exhibit a functional paradox—both anti-frailty/anti-inflammatory and pro-neutrophilic proliferation. Single-cell analysis revealed that this paradox originates from the functional differentiation of the module in macrophages (protective clearance) and progenitor cells (myeloid proliferation), manifesting as a systemic decoupling of "clearance intent" and "metabolic support." Based on these findings, the original theory of "Programmatic Adaptive Failure" was proposed, and the POAM score and FIRE-AI decision system were developed, completing the translational loop from mechanism to clinical application. Conclusion This study establishes systemic inflammation as a significant mediator in frailty-driven aging and discovers a novel myeloid-based "Programmatic Adaptive Failure" mechanism. Our work provides both a new theoretical framework for understanding inflammaging and a translatable toolkit (POAM score & FIRE-AI) for stratifying risk and guiding targeted interventions to break the frailty-inflammation-aging cycle.