Biological Age, Chronological Age, and Survival in Pulmonary Fibrosis: A Causal Mediation Analysis

Abstract

Rationale: Accelerated biological aging has been implicated in the development of interstitial lung disease (ILD) and other diseases of aging but remains poorly understood. Objectives: To identify plasma proteins that mediate the relationship between chronological age and survival association in patients with ILD. Methods: Causal mediation analysis was performed to identify plasma proteins that mediated the chronological age-survival relationship in an idiopathic pulmonary fibrosis discovery cohort. Proteins mediating this relationship after adjustment for false discovery were advanced for testing in an independent ILD validation cohort and explored in a chronic obstructive pulmonary disease cohort. A proteomic-based measure of biological age was constructed and survival analysis performed, assessing the impact of biological age and peripheral blood telomere length on the chronological age-survival relationship. Measurements and Main Results: Twenty-two proteins mediated the chronological age-survival relationship after adjustment for false discovery in the idiopathic pulmonary fibrosis discovery cohort (n = 874), with 19 remaining significant mediators of this relationship in the ILD validation cohort (n = 983) and one mediating this relationship in the chronic obstructive pulmonary disease cohort. Latent transforming growth factor-β binding protein 2 and ectodysplasin A2 receptor showed the strongest mediation across cohorts. A proteomic measure of biological age completely attenuated the chronological age-survival association and better discriminated survival than chronological age. Results were robust to adjustment for peripheral blood telomere length, which did not mediate the chronological age-survival relationship. Conclusions: Molecular measures of aging completely mediate the relationship between chronological age and survival, suggesting that chronological age has no direct effect on ILD survival.

Keywords: age; causal mediation; idiopathic pulmonary fibrosis; proteomics.

Figure 1.

Causal diagrams depicting the relationship between exposure, outcome, and mediator (A), hypothesized relationship between chronological age, biological age, and survival, whereby biologic age completely mediates the association between chronological age and idiopathic pulmonary fibrosis survival (B) and specific model to test this hypothesis, whereby the direct and indirect (via aging biomarkers) effects of chronological age on survival are estimated after adjustment for covariates that are potentially influenced by chronological age and also confound the mediator–outcome relationship (C). ILD = interstitial lung disease.

Figure 2.

Distribution (A) and correlation (B) between measures of observed chronologic age and proteomic-derived, biological age.

Figure 3.

Kaplan-Meier survival curves for biological age categories stratified by chronological age category (A–C) and for chronological age categories stratified by biological age category (D–F).