The availability of proteomics data in large, population-based cohort studies offers an unprecedented opportunity to understand the onset and progression of aging-related diseases and syndromes. We examined the proteomic signature of the onset of frailty and the progression to death among the prefrail and frail. A total of 2920 proteins were assayed using Olink among 43,895 participants (aged 39–70 years) in the UK Biobank. Using multinomial logistic models, we identified 102 and 90 proteins cross-sectionally associated with baseline prefrailty and frailty (Bonferroni-corrected p-value < 0.05), respectively. Additionally, cox regression identified 87 and 48 proteins associated with death among initially prefrail (n = 16,661) and frail (n = 1647) individuals, respectively. Eight overlapping proteins were cross-sectionally associated with prefrailty and frailty at baseline and prospectively associated with death among prefrail and frail individuals. CD300E, GDF15, and PLAUR were the most significant proteins among these eight proteins. LASSO regression selected 73 and 23 proteins predicting death in prefrail and frail participants, respectively. Protein-based prediction models based on LASSO regression and the light gradient boosting machine classifier demonstrated satisfactory discrimination, calibration, and reclassification among the prefrail and frail. GDF15, WFDC2, and NEFL were the most important proteins predicting death among prefrail and frail individuals. Proteins associated with the onset and progression of prefrailty and frailty were enriched in pathways involving protein metabolism, cellular signaling in disease, apoptosis, and inflammation. Our research could uncover novel therapeutic targets for addressing the onset and progression of frailty, potentially informing the design of patient-centered treatment strategies and management plans.

在基于人群的大型队列研究中，蛋白质组学数据的可用性为了解衰老相关疾病和综合征的发生和发展提供了前所未有的机会。我们检查了虚弱前期和虚弱者发病的蛋白质组学特征以及进展至死亡。在英国生物样本库中的 43,895 名参与者（年龄 39-70 岁）中，使用 Olink 共检测了 2920 种蛋白质。使用多项式 logistic 模型，我们分别鉴定了 102 个和 90 个与基线脆弱性和脆弱性横断面相关的蛋白质 （Bonferroni 校正的 p 值 < 0.05）。此外，cox 回归分析在最初虚弱 （n = 16,661） 和虚弱 （n = 1647） 个体中分别发现了 87 种和 48 种与死亡相关的蛋白质。8 个重叠的蛋白质在横断面上与基线时的脆弱性和脆弱性相关，并且前瞻性地与脆弱和脆弱个体的死亡相关。CD300E、GDF15 和 PLAUR 是这 8 种蛋白中最重要的蛋白。LASSO 回归选择了 73 种和 23 种蛋白质，分别预测虚弱和虚弱参与者的死亡。基于 LASSO 回归和光梯度提升机器分类器的基于蛋白质的预测模型表明，在早期虚弱和虚弱之间具有令人满意的区分、校准和重新分类。GDF15 、 WFDC2 和 NEFL 是预测体弱前期和体弱个体死亡的最重要蛋白。与易碎和衰弱发生进展相关的蛋白质富集在涉及蛋白质代谢、疾病中的细胞信号传导、细胞凋亡和炎症的通路中。 我们的研究可以发现解决虚弱发生和发展的新型治疗靶点，从而可能为以患者为中心的治疗策略和管理计划的设计提供信息。