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; pprefrailty = 1 × 10−15, pfrailty = 2 × 10−19), transgelin (TAGLN; pprefrailty = 2 × 10−12, pfrailty = 6 × 10−22), and insulin‐like growth factor‐binding protein 2 (IGFBP2; pprefrailty = 5 × 10−15, pfrailty = 1 × 10−15) and with a lower level of growth hormone receptor (GHR, pprefrailty = 3 × 10−16, pfrailty = 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.

High Throughput Plasma Proteomics and Risk of Heart Failure and Frailty in Late Life

“…These findings are consistent with the greater number of candidate proteins associated with incident HFpEF compared with incident HFrEF. The relationship between frailty and HF is likely bidirectional . While fibrosis, inflammation, and cell death have been implicated in both HFpEF and HFrEF and frailty is associated with similar risk of incident HFpEF and HFrEF, our findings suggest that the pathways leading to the development of frailty and HF are more closely shared between frailty and HFpEF than HFrEF.…”

“…Follistatin-like 3 (FSTL3) has been associated with risk of HF . TREM1, a known predictor of clinical frailty, has been implicated in atherogenesis and is associated with mortality in MI though upregulation of inflammatory cytokines promoting fibrosis . However, the inconsistent MR findings with respect to genetic effects on HF and cardiac structure raise questions regarding this finding.…”