Immune-cell Redistribution Explains Transcriptomic Aging Signatures During Severe Infection
Fabiano Pinheiro da Silva1, Marcel Cerqueira César Machado1
1University of São Paulo Faculty of Medicine, Emergency Medicine Department, São Paulo, Brazil.
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.