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Pro-Inflammatory Proteins Associated with Frailty and Its Progression—A Longitudinal Study in Community-Dwelling Women

Mitchell, Adam LU ; Malmgren, Linnea LU orcid ; Bartosch, Patrik LU ; McGuigan, Fiona Elizabeth LU orcid and Akesson, Kristina E. LU (2023) In Journal of Bone and Mineral Research 38(8). p.1076-1091
Abstract

The complex pathophysiology underlying biological aging creates challenges for identifying biomarkers associated with frailty. This longitudinal, nontargeted proteomics study aimed to identify proteins associated with frailty, particularly the change from nonfrail to frail. The population-based Osteoporosis Prospective Risk Assessment cohort includes women all of whom are 75 years old at inclusion (n = 1044) and reassessed at 80 years (n = 715) and 85 years (n = 382). A deficits in health frailty index (FI) and 92 plasma proteins (Olink CVD-II panel) were available at all ages. The identical age facilitated differentiating chronological and biological aging. Bidirectional analyses, performed cross-sectionally and longitudinally, used... (More)

The complex pathophysiology underlying biological aging creates challenges for identifying biomarkers associated with frailty. This longitudinal, nontargeted proteomics study aimed to identify proteins associated with frailty, particularly the change from nonfrail to frail. The population-based Osteoporosis Prospective Risk Assessment cohort includes women all of whom are 75 years old at inclusion (n = 1044) and reassessed at 80 years (n = 715) and 85 years (n = 382). A deficits in health frailty index (FI) and 92 plasma proteins (Olink CVD-II panel) were available at all ages. The identical age facilitated differentiating chronological and biological aging. Bidirectional analyses, performed cross-sectionally and longitudinally, used regression models controlled for false discovery rate (FDR), across 5- and 10-year time windows and longitudinal mixed models. Frailty outcomes were frailty index, frailty status (frail defined as FI ≥ 0.25), change in frailty index, and change in frailty status, together with protein expression or change in protein expression. Elevated levels of 32 proteins were positively associated with the FI, cross-sectionally at all ages (range: β-coefficients 0.22–2.06; FDR 0.021–0.024), of which 18 were also associated with frailty status (range: odds ratios 1.40–5.77; FDR 0.022–0.016). Based on the accrued data, eight core proteins (CD4, FGF23, Gal-9, PAR-1, REN, TNFRSF10A TNFRSF11A, and TNFRSF10B) are proposed. A one-unit change in the FI was additively associated with increased protein expression over 5 and 10 years (range: β-coefficients 0.52–1.59; p < 0.001). Increments in baseline FI consistently associated with a change in protein expression over time (5 years, β-range 0.05–1.35; 10 years, β-range 0.51–1.48; all p < 0.001). A one-unit increase in protein expression was also associated with an increased probability of being frail (FI ≥ 0.25) (β-range: 0.14–0.61). Mirroring the multisystem deterioration that typifies frailty, the proteins and their associated biological pathways reflect pathologies, including the renal system, skeletal homeostasis, and TRAIL-activated apoptotic signaling. The core proteins are compelling candidates for understanding the development and progression of frailty with advancing age, including the intrinsic musculoskeletal component.

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author
; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
aging, biomarker, frailty, longitudinal, Olink, protein, proteomics
in
Journal of Bone and Mineral Research
volume
38
issue
8
pages
16 pages
publisher
Wiley-Blackwell
external identifiers
  • pmid:37254268
  • scopus:85165423566
ISSN
0884-0431
DOI
10.1002/jbmr.4861
language
English
LU publication?
yes
id
edde4cf8-8072-4200-a767-71e639d5de33
date added to LUP
2023-09-19 15:24:40
date last changed
2024-04-19 01:28:01
@article{edde4cf8-8072-4200-a767-71e639d5de33,
  abstract     = {{<p>The complex pathophysiology underlying biological aging creates challenges for identifying biomarkers associated with frailty. This longitudinal, nontargeted proteomics study aimed to identify proteins associated with frailty, particularly the change from nonfrail to frail. The population-based Osteoporosis Prospective Risk Assessment cohort includes women all of whom are 75 years old at inclusion (n = 1044) and reassessed at 80 years (n = 715) and 85 years (n = 382). A deficits in health frailty index (FI) and 92 plasma proteins (Olink CVD-II panel) were available at all ages. The identical age facilitated differentiating chronological and biological aging. Bidirectional analyses, performed cross-sectionally and longitudinally, used regression models controlled for false discovery rate (FDR), across 5- and 10-year time windows and longitudinal mixed models. Frailty outcomes were frailty index, frailty status (frail defined as FI ≥ 0.25), change in frailty index, and change in frailty status, together with protein expression or change in protein expression. Elevated levels of 32 proteins were positively associated with the FI, cross-sectionally at all ages (range: β-coefficients 0.22–2.06; FDR 0.021–0.024), of which 18 were also associated with frailty status (range: odds ratios 1.40–5.77; FDR 0.022–0.016). Based on the accrued data, eight core proteins (CD4, FGF23, Gal-9, PAR-1, REN, TNFRSF10A TNFRSF11A, and TNFRSF10B) are proposed. A one-unit change in the FI was additively associated with increased protein expression over 5 and 10 years (range: β-coefficients 0.52–1.59; p &lt; 0.001). Increments in baseline FI consistently associated with a change in protein expression over time (5 years, β-range 0.05–1.35; 10 years, β-range 0.51–1.48; all p &lt; 0.001). A one-unit increase in protein expression was also associated with an increased probability of being frail (FI ≥ 0.25) (β-range: 0.14–0.61). Mirroring the multisystem deterioration that typifies frailty, the proteins and their associated biological pathways reflect pathologies, including the renal system, skeletal homeostasis, and TRAIL-activated apoptotic signaling. The core proteins are compelling candidates for understanding the development and progression of frailty with advancing age, including the intrinsic musculoskeletal component.</p>}},
  author       = {{Mitchell, Adam and Malmgren, Linnea and Bartosch, Patrik and McGuigan, Fiona Elizabeth and Akesson, Kristina E.}},
  issn         = {{0884-0431}},
  keywords     = {{aging; biomarker; frailty; longitudinal; Olink; protein; proteomics}},
  language     = {{eng}},
  number       = {{8}},
  pages        = {{1076--1091}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{Journal of Bone and Mineral Research}},
  title        = {{Pro-Inflammatory Proteins Associated with Frailty and Its Progression—A Longitudinal Study in Community-Dwelling Women}},
  url          = {{http://dx.doi.org/10.1002/jbmr.4861}},
  doi          = {{10.1002/jbmr.4861}},
  volume       = {{38}},
  year         = {{2023}},
}