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 × 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.