Late‐life plasma proteins associated with prevalent and incident frailty: A proteomic analysis

Abstract Proteomic approaches have unique advantages in the identification of biological pathways that influence physical frailty, a multifactorial geriatric syndrome predictive of adverse health outcomes in older adults. To date, proteomic studies of frailty are scarce, and few evaluated prefrailty as a separate state or examined predictors of incident frailty. Using plasma proteins measured by 4955 SOMAmers in the Atherosclerosis Risk in Community study, we identified 134 and 179 proteins cross‐sectionally associated with prefrailty and frailty, respectively, after Bonferroni correction ( p < 1 × 10 −5 ) among 3838 older adults aged ≥65 years, adjusting for demographic and physiologic factors and chronic diseases. Among them, 23 (17%) and 82 (46%) were replicated in the Cardiovascular Health Study using the same models (FDR p < 0.05). Notably, higher odds of prefrailty and frailty were observed with higher levels of growth differentiation factor 15 (GDF15; p prefrailty = 1 × 10 −15 , p frailty = 2 × 10 −19 ), transgelin (TAGLN; p prefrailty = 2 × 10 −12 , p frailty = 6 × 10 −22 ), and insulin‐like growth factor‐binding protein 2 (IGFBP2; p prefrailty = 5 × 10 −15 , p frailty = 1 × 10 −15 ) and with a lower level of growth hormone receptor (GHR, p prefrailty = 3 × 10 −16 , p frailty = 2 × 10 −18 ). Longitudinally, we identified 4 proteins associated with incident frailty ( p < 1 × 10 −5 ). Higher levels of triggering receptor expressed on myeloid cells 1 (TREM1), TAGLN, and heart and adipocyte fatty‐acid binding proteins predicted incident frailty. Differentially regulated proteins were enriched in pathways and upstream regulators related to lipid metabolism, angiogenesis, inflammation, and cell senescence. Our findings provide a set of plasma proteins and biological mechanisms that were dysregulated in both the prodromal and the clinical stage of frailty, offering new insights into frailty etiology and targets for intervention.