Proteins in the pathway from high red blood cell width distribution to all-cause mortality

Yusuke Osawa, Toshiko Tanaka, Richard D. Semba, Giovanna Fantoni, Ruin Moaddel, Julián Candia, Eleanor M. Simonsick, Stefania Bandinelli, Luigi Ferrucci

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)


Background: The pathophysiological mechanisms underlying the association between red blood cell distribution width (RDW) and all-cause mortality are unknown. We conducted a data-driven discovery investigation to identify plasma proteins that mediate the association between RDW and time to death in community-dwelling adults. Methods: At baseline, 962 adults (women, 54·4%; age range, 21–98 years) participated in the InCHIANTI, “Aging in the Chianti Area” study, and proteomics data were generated from their plasma specimens. Of these, 623 participants had proteomics data available at the 9-year follow-up. For each visit, a total of 1301 plasma proteins were measured using SOMAscan technology. Complete data on vital status were available up to the 15-year follow-up period. Protein-specific exponential distribution accelerated failure time, and linear regression analyses adjusted for possible covariates were used for mortality and mediation analyses, respectively (survival data analysis). Findings: Baseline values of EGFR, GHR, NTRK3, SOD2, KLRF1, THBS2, TIMP1, IGFBP2, C9, APOB, and LRP1B mediated the association between baseline RDW and all-cause mortality. Changes in IGFBP2 and C7 over 9 years mediated the association between changes in RDW and 6-year all-cause mortality. Interpretation: Cellular senescence may contribute to the association between RDW and mortality. Funding: This study was funded by grants from the National Institutes of Health (NIH) and the National Institute on Aging (NIA) contract and was supported by the Intramural Research Program of the NIA, NIH. The InCHIANTI study was supported as a ‘targeted project’ by the Italian Ministry of Health and in part by the U.S. NIA.

Original languageEnglish
Article number103816
Publication statusPublished - 2022 Feb


  • Aging
  • Insulin-like growth factor-binding protein 2
  • Mortality
  • Proteomics
  • Red blood cell distribution width

ASJC Scopus subject areas

  • General Biochemistry,Genetics and Molecular Biology


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