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

doi:10.1164/rccm.202007-2993OC

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 journal › Article › peer-review

59 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 language	English (US)
Pages (from-to)	1149-1157
Number of pages	9
Journal	American Journal of Respiratory and Critical Care Medicine
Volume	203
Issue number	9
DOIs	https://doi.org/10.1164/rccm.202007-2993OC
State	Published - May 1 2021
Externally published	Yes

Keywords

Aging
GDF15
Idiopathic pulmonary fibrosis
Interstitial lung abnormalities
Mortality

ASJC Scopus subject areas

Pulmonary and Respiratory Medicine
Critical Care and Intensive Care Medicine

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10.1164/rccm.202007-2993OC

Cite this

Sanders, J. L., Putman, R. K., Dupuis, J., Xu, H., Murabito, J. M., Araki, T., Nishino, M., Benjamin, E. J., Levy, D. L., Ramachandran, V. S., Washko, G. R., Curtis, J. L., Freeman, C. M., Bowler, R. P., Hatabu, H., O’Connor, G. T., & Hunninghake, G. M. (2021). The association of aging biomarkers, interstitial lung abnormalities, and mortality. American Journal of Respiratory and Critical Care Medicine, 203(9), 1149-1157. https://doi.org/10.1164/rccm.202007-2993OC

Sanders, JL, Putman, RK, Dupuis, J, Xu, H, Murabito, JM, Araki, T, Nishino, M, Benjamin, EJ, Levy, DL, Ramachandran, VS, Washko, GR, Curtis, JL, Freeman, CM, Bowler, RP, Hatabu, H, O’Connor, GT & Hunninghake, GM 2021, 'The association of aging biomarkers, interstitial lung abnormalities, and mortality', American Journal of Respiratory and Critical Care Medicine, vol. 203, no. 9, pp. 1149-1157. https://doi.org/10.1164/rccm.202007-2993OC

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title = "The association of aging biomarkers, interstitial lung abnormalities, and mortality",

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.",

keywords = "Aging, GDF15, Idiopathic pulmonary fibrosis, Interstitial lung abnormalities, Mortality",

author = "Sanders, {Jason L.} and Putman, {Rachel K.} and Jos{\'e}e Dupuis and Hanfei Xu and Murabito, {Joanne M.} and Tetsuro Araki and Mizuki Nishino and Benjamin, {Emelia J.} and Levy, {Daniel L.} and Ramachandran, {Vasan S.} and Washko, {George R.} and Curtis, {Jeffrey L.} and Freeman, {Christine M.} and Bowler, {Russell P.} and Hiroto Hatabu and O{\textquoteright}Connor, {George T.} and Hunninghake, {Gary M.}",

note = "Publisher Copyright: Copyright {\textcopyright} 2021 by the American Thoracic Society",

year = "2021",

month = may,

day = "1",

doi = "10.1164/rccm.202007-2993OC",

language = "English (US)",

volume = "203",

pages = "1149--1157",

journal = "American Journal of Respiratory and Critical Care Medicine",

issn = "1073-449X",

publisher = "American Thoracic Society",

number = "9",

}

TY - JOUR

T1 - The association of aging biomarkers, interstitial lung abnormalities, and mortality

AU - Sanders, Jason L.

AU - Putman, Rachel K.

AU - Dupuis, Josée

AU - Xu, Hanfei

AU - Murabito, Joanne M.

AU - Araki, Tetsuro

AU - Nishino, Mizuki

AU - Benjamin, Emelia J.

AU - Levy, Daniel L.

AU - Ramachandran, Vasan S.

AU - Washko, George R.

AU - Curtis, Jeffrey L.

AU - Freeman, Christine M.

AU - Bowler, Russell P.

AU - Hatabu, Hiroto

AU - O’Connor, George T.

AU - Hunninghake, Gary M.

PY - 2021/5/1

Y1 - 2021/5/1

N2 - 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.

AB - 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.

KW - Aging

KW - GDF15

KW - Idiopathic pulmonary fibrosis

KW - Interstitial lung abnormalities

KW - Mortality

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

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