Current Aging Science · Oct 26, 2026
Immune-cell Redistribution Explains Transcriptomic Aging Signatures During Severe Infection
By da Silva FP, Machado MCC
Introduction/Objective: Severe infection alters whole-blood transcriptomic profiles, potentially affecting RNA-based biological age estimates. We investigated whether transcriptomic aging signatures during severe infection are associated with changes in leukocyte composition. Methods: Two publicly available RNA-sequencing cohorts were analyzed: severe COVID-19 (GSE152641; 62 patients, 24 healthy controls) and severe non-COVID-19 pneumonia (GSE196399; 56 patients, 21 healthy controls). Transcriptomic age was estimated using the blood-specific RNAAgeCalc model. Disease associations were evaluated using age- and sexadjusted regression models, followed by additional adjustment for leukocyte fractions computationally inferred using quanTIseq. Composition-adjusted gene-level and pathway-level age associations were also examined. Results: Both infections were associated with increased transcriptomic age acceleration (COVID-19: β = 4.92 years, p = 0.033; non-COVID-19 pneumonia: β = 7.94 years, p < 0.001). Following adjustment for inferred neutrophil, monocyte, and lymphocyte fractions, the association was no longer statistically significant in COVID-19 (p = 0.45) and attenuated in pneumonia (p = 0.079). Transcriptomic age acceleration tracked the inferred neutrophil–lymphocyte axis. Residual age-associated pathways included heme metabolism, E2F targets, G2M checkpoint, and epithelial–mesenchymal transition. Discussion: These findings suggest that whole-blood transcriptomic aging estimates during severe infection are sensitive to inferred leukocyte composition, although shared transcriptomic inputs preclude causal attribution. Conclusion: Immune-cell composition should be considered when interpreting blood transcriptomic aging clocks during severe infection. Residual age-associated pathways warrant further cell-resolved investigation.