Novel proteomic subtypes of frailty with distinct molecular patterns and prognosis

IF 3.6 2区医学 Q2 GERIATRICS & GERONTOLOGY

Maturitas Pub Date : 2026-03-01 Epub Date: 2026-01-25 DOI:10.1016/j.maturitas.2026.108851

Zhenyi Xu , Ce Wang , Jiaofeng Wang , Jie Chen , Xiaojun Wang , Zhijun Bao , Yan Zhang

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引用次数: 0

Abstract

Objectives

The frailty phenotype has limitations in capturing the biological heterogeneity of the condition. Our study identified subtypes of frailty based on proteomics and examined their associations with several adverse outcomes.

Method

The study included 1513 frail individuals and 29,339 non-frail individuals from the UK Biobank and analyzed 2920 proteins. Unsupervised K-means clustering was applied to identify molecular subtypes of frailty and the Boruta algorithm was applied to identify the key proteins for distinguishing these subtypes.

Results

Four novel subtypes were identified among frail individuals: S1 (n = 403), S2 (n = 209), S3 (n = 587) and S4 (n = 314). In total, 567 key proteins for distinguishing subtypes were identified, in diverse biological pathways. Each subtype exhibited distinct molecular characteristics. S1 was characterized by elevated genomic instability, S2 by altered intercellular communication, S3 by broad upregulation of aging-related features, and S4 by loss of proteostasis and mitochondrial dysfunction. While the prognosis of S3 was similar to S1, S2 and S4 had a worse prognosis than S1. S2, in particular, presented a significantly increased risk of multiple adverse outcomes compared with S1, including all-cause mortality (hazard ratio 2.13; 95% confidence interval 1.60–2.85), cardiovascular disease (hazard ratio 1.78; 95% confidence interval 1.00–3.17), respiratory disease (hazard ratio 1.83; 95% confidence interval 1.24–2.70), kidney disease (hazard ratio 2.76; 95% confidence interval 1.57–4.85), liver disease (hazard ratio 6.19; 95% confidence interval 4.13–9.29), and cancer (hazard ratio 2.06; 95% confidence interval 1.43–2.96).

Conclusion

Our study identified four proteomic subtypes of frailty with distinct molecular signatures and differential prognostic implications, highlighting the biological heterogeneity of frailty and the need for personalized medicine and management strategies.

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具有不同分子模式和预后的脆弱的新蛋白质组亚型

目的脆弱表型在捕捉疾病的生物学异质性方面存在局限性。我们的研究基于蛋白质组学确定了虚弱的亚型，并检查了它们与几种不良后果的关联。方法从英国生物银行（UK Biobank）中选取1513名体弱个体和29339名非体弱个体，分析2920种蛋白质。采用无监督K-means聚类方法鉴定脆性的分子亚型，并采用Boruta算法鉴定区分这些亚型的关键蛋白。结果在体弱个体中鉴定出4种新的亚型：S1 （n = 403）、S2 （n = 209）、S3 （n = 587）和S4 （n = 314）。在不同的生物学途径中，共鉴定出567种用于区分亚型的关键蛋白。每个亚型都表现出不同的分子特征。S1表现为基因组不稳定性升高，S2表现为细胞间通讯改变，S3表现为衰老相关特征的广泛上调，S4表现为蛋白质平衡丧失和线粒体功能障碍。S3的预后与S1相似，S2和S4的预后较S1差。特别是S2，与S1相比，多种不良结局的风险显著增加，包括全因死亡率（风险比2.13,95%置信区间1.60-2.85）、心血管疾病（风险比1.78,95%置信区间1.00-3.17）、呼吸系统疾病（风险比1.83,95%置信区间1.24-2.70）、肾脏疾病（风险比2.76,95%置信区间1.57-4.85）、肝脏疾病(风险比6.19；95%可信区间4.13-9.29)和癌症（风险比2.06；95%可信区间1.43-2.96）。我们的研究确定了虚弱的四种蛋白质组亚型，它们具有不同的分子特征和不同的预后意义，突出了虚弱的生物学异质性以及个性化医疗和管理策略的必要性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Maturitas 医学-妇产科学

CiteScore

9.10

自引率

2.00%

发文量

142

审稿时长

40 days

期刊介绍： Maturitas is an international multidisciplinary peer reviewed scientific journal of midlife health and beyond publishing original research, reviews, consensus statements and guidelines, and mini-reviews. The journal provides a forum for all aspects of postreproductive health in both genders ranging from basic science to health and social care. Topic areas include:• Aging• Alternative and Complementary medicines• Arthritis and Bone Health• Cancer• Cardiovascular Health• Cognitive and Physical Functioning• Epidemiology, health and social care• Gynecology/ Reproductive Endocrinology• Nutrition/ Obesity Diabetes/ Metabolic Syndrome• Menopause, Ovarian Aging• Mental Health• Pharmacology• Sexuality• Quality of Life