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

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 x 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 x 10(-15), p(frailty) = 2 x 10(-19)), transgelin (TAGLN; p(prefrailty) = 2 x 10(-12), p(frailty )= 6 x 10(-22)), and insulin-like growth factor-binding protein 2 (IGFBP2; p(prefrailty) = 5 x 10(-15), p(frailty) = 1 x 10(-15)) and with a lower level of growth hormone receptor (GHR, p(prefrailty) = 3 x 10(-16), p(frailty) = 2 x 10(-18)). Longitudinally, we identified 4 proteins associated with incident frailty (p < 1 x 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.