Programmatic adaptive failure in myeloid cells: a hypothesis-generating framework linking frailty to accelerated epigenetic aging

Abstract Frailty is associated with accelerated epigenetic aging, but mechanisms driving the “frailty-inflammation-aging” cycle remain unclear. Using NHANES (1999–2002, N = 2519), frailty was positively associated with accelerated epigenetic aging, with inflammation mediating ~17.2%; updated cycles supported distributional comparability of the IBI; CRP sensitivity analysis gave ~19.6%. Two-step Mendelian randomization suggested a “frailty→neutrophilia→accelerated aging” genetically associated pathway (indirect effect 0.309, P < 0.001). WGCNA identified a 529-gene BLUE module; external single-cell data supported myeloid enrichment (503/513 genes matched); transcription factor analysis implicated TFEB/TFE3 as upstream regulators. A three-gene score (the B3 score (BLUE 3‑gene score)) from this module correlated positively with FI ( r = 0.272) and IBI ( r = 0.306) and was higher in high-frailty groups ( P = 0.003). Single-cell analysis suggested cell-type distribution patterns of the module across macrophages and myeloid progenitors. We suggest that these associations may arise from shared biological processes. Based on these findings, we propose myeloid ‘programmatic adaptive failure’ as a hypothesis‑generating framework and an exploratory prototype (FIRE‑AI) integrating the inflammatory threshold, the B3 gene score, and network pharmacology.