Pro-inflammatory proteins associated with frailty and its progression - a longitudinal study in community dwelling women.

The complex pathophysiology underlying biological ageing creates challenges for identifying biomarkers associated with frailty. This longitudinal, non-targeted proteomics study aims to identify proteins associated with frailty, particularly the change from non-frail to frail. The population based OPRA cohort is women, all age 75y at inclusion (n=1044); reassessed at 80y (n=715) and 85y (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 facilitates differentiating chronological and biological aging. Bi-directional analyses, performed cross-sectionally and longitudinally, used regression models controlled for false discovery rate (FDR), across 5-year and 10-year time-windows and longitudinal mixed models. Frailty outcomes were 'frailty index', 'frail status (frail 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 frailty index, cross-sectionally at all ages (range: β-coefficients 0.22-2.06; FDR 0.021-0.024), of which 18 were also associated with frail 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 suggested. A one unit change in frailty index additively associated with increased protein expression over 5-years and 10-years (range: β-coefficients 0.52-1.59; p<0.001). Increments in baseline frailty index consistently associated with 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 multi-system deterioration that typifies frailty, the proteins and their associated biological pathways reflect pathologies including the renal system, skeletal homeostasis and TRAIL-activated apoptotic signaling was enriched. The core proteins, are convincing candidates in understanding the development and progression of frailty with advancing age, including the intrinsic musculoskeletal component. This article is protected by copyright. All rights reserved.