The association of aging biomarkers, interstitial lung abnormalities, and mortality

Jason L. Sanders, Rachel K. Putman, Josée Dupuis, Hanfei Xu, Joanne M. Murabito, Tetsuro Araki, Mizuki Nishino, Emelia J. Benjamin, Daniel L. Levy, Vasan S. Ramachandran, George R. Washko, Jeffrey L. Curtis, Christine M. Freeman, Russell P. Bowler, Hiroto Hatabu, George T. O’Connor, Gary M. Hunninghake

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Rationale: 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. Objectives: To evaluate the associations among aging biomarkers, ILA, and all-cause mortality. Methods: In the FHS (Framingham Heart Study), we evaluated associations among plasma biomarkers (IL-6, CRP [C-reactive protein], TNFR [tumor necrosis factor a 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. Measurements and Main Results: 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]; P = 0.0002), TNFR (3.1 [1.6–5.8]; P = 0.004), IL-6 (1.8 [1.4–2.4]; P < 0.0001), and CRP (1.7 [1.3–2.0]; P < 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]; P = 0.02), TNFR (1.8 [1.0–3.3]; P = 0.05), and IGFBP1 (1.3 [1.1–1.7]; P = 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]; P < 0.0001) and mortality (hazard ratio, 1.6 [1.1–2.2]; P = 0.01). Causal inference analysis showed that the association of age with ILA was mediated by IL-6 (P < 0.0001) and TNFR (P = 0.002) and was likely mediated by GDF15 (P = 0.008) in the FHS and was mediated by GDF15 (P = 0.001) in the COPDGene Study. Conclusions: Some aging-related biomarkers are associated with ILA. GDF15, in particular, may explain some of the associations among age, ILA, and mortality.

Original languageEnglish (US)
Pages (from-to)1149-1157
Number of pages9
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume203
Issue number9
DOIs
StatePublished - May 1 2021
Externally publishedYes

Keywords

  • Aging
  • GDF15
  • Idiopathic pulmonary fibrosis
  • Interstitial lung abnormalities
  • Mortality

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine
  • Pulmonary and Respiratory Medicine

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