Aging reshapes post-traumatic immune trajectories: selective human recovery associations and complementary NAD⁺-sensitive endothelial responses

Abstract Background Aging affects immunity after severe injury, but its effects on the timing of post-traumatic immune remodeling and subsequent recovery remain unclear. We examined age-associated trajectories and NAD⁺-sensitive endothelial remodeling as complementary evidence. Methods We analyzed public mouse polytrauma, longitudinal human trauma, clinical recovery, brain endothelial aging, and published NAD⁺ perturbation datasets. Fixed immune programmes, a mouse-derived signature frozen before human testing, strict ortholog mapping, outcome-linked survival models, and sensitivity analyses were applied without pooling datasets. Results In 36 young and aged mice, immune programme differences peaked at day 1, whereas aged animals remained farther from age-matched transcriptomic baseline at day 3. A 311-gene late-response signature comprised 188 old-excess and 123 old-deficit genes. Neither component distinguished fast from slow human recovery at day 3 after correction, but day-7 old-excess scores were associated with slower subsequent recovery (hazard ratio 0.605, 95% confidence interval 0.469–0.780; adjusted q = 0.0010). Independent brain endothelial analyses revealed heterogeneous redox and barrier-associated transcription. In a published HUVEC model, NAMPT inhibition reduced endothelial transition projection to approximately 0.53, whereas nicotinamide mononucleotide restored it to approximately 1.05. Twenty-one Hallmark pathways met blockade–rescue criteria; only oxidative phosphorylation met strict cross-context criteria in a separate hippocampal model. Conclusions Aging was associated with a distinct late post-traumatic immune state showing selective, time-dependent links to human recovery. NAD⁺-sensitive endothelial remodeling provides independent mechanistic context, not evidence of causation in trauma recovery.