The Association of Aging Biomarkers, Interstitial Lung Abnormalities, and Mortality

Abstract

<b>Rationale:</b> The association between aging and idiopathic pulmonary fibrosis has been established. The associations between aging-related biomarkers and interstitial lung abnormalities (ILA) have not been comprehensively evaluated.<b>Objectives:</b> To evaluate the associations among aging biomarkers, ILA, and all-cause mortality.<b>Methods:</b> In the FHS (Framingham Heart Study), we evaluated associations among plasma biomarkers (IL-6, CRP [C-reactive protein], TNFR [tumor necrosis factor α receptor II], GDF15 [growth differentiation factor 15], cystatin-C, HGBA1C [Hb A1C], insulin, IGF1 [insulin-like growth factor 1], and IGFBP1 [IGF binding protein 1] and IGFBP3]), ILA, and mortality. Causal inference analysis was used to determine whether biomarkers mediated age. GDF15 results were replicated in the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) Study.<b>Measurements and Main Results:</b> In the FHS, there were higher odds of ILA per increase in natural log-transformed GDF15 (odds ratio [95% confidence interval], 3.4 [1.8-6.4]; <i>P</i> = 0.0002), TNFR (3.1 [1.6-5.8]; <i>P</i> = 0.004), IL-6 (1.8 [1.4-2.4]; <i>P</i> < 0.0001), and CRP (1.7 [1.3-2.0]; <i>P</i> < 0.0001). In the FHS, after adjustment for multiple comparisons, no biomarker was associated with increased mortality, but the associations of GDF15 (hazard ratio, 2.0 [1.1-3.5]; <i>P</i> = 0.02), TNFR (1.8 [1.0-3.3]; <i>P</i> = 0.05), and IGFBP1 (1.3 [1.1-1.7]; <i>P</i> = 0.01) approached significance. In the COPDGene Study, higher natural log-transformed GDF15 was associated with ILA (odds ratio, 8.1 [3.1-21.4]; <i>P</i> < 0.0001) and mortality (hazard ratio, 1.6 [1.1-2.2]; <i>P</i> = 0.01). Causal inference analysis showed that the association of age with ILA was mediated by IL-6 (<i>P</i> < 0.0001) and TNFR (<i>P</i> = 0.002) and was likely mediated by GDF15 (<i>P</i> = 0.008) in the FHS and was mediated by GDF15 (<i>P</i> = 0.001) in the COPDGene Study.<b>Conclusions:</b> Some aging-related biomarkers are associated with ILA. GDF15, in particular, may explain some of the associations among age, ILA, and mortality.