Zhang Xin, Ma Sisi, Naz Syeda Iffat, Soderblom Erik J, Aliferis Constantin, Kraus Virginia Byers
Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, 27701, USA.
Department of Orthopaedic Surgery, Duke University School of Medicine, Durham, NC, 27701, USA.
Geroscience. 2025 Apr;47(2):1455-1469. doi: 10.1007/s11357-024-01454-z. Epub 2024 Dec 18.
Extracellular vesicles (EVs) play crucial roles in aging. In this National Institutes on Aging-funded study, we sought to identify circulating extracellular vesicle (EV) biomarkers indicative of longevity. The plasma EV proteome of 48 older adults (mean age 77.2 ± 1.7 years [range 72-80]; 50% female, 50% Black, 50% < 2-year survival, 50% ≥ 10-year survival) was analyzed by high-resolution mass spectrometry and flow cytometry. The ability of EV peptides to predict longevity was evaluated in discovery (n = 32) and validation (n = 16) datasets with areas under receiver operating characteristic curves (AUCs). Longevity-associated large EV (LEV) plasma subpopulations were mainly related to immune cells (HLA-ABC, CD9, and CD31) and muscle cells (MCAD and RyR2). Of 7960 identified plasma EV peptides (519 proteins), 46.4% were related to the immune system and 10.1% to muscle. Compared with short-lived older adults, 756 EV peptides (131 proteins) had a higher abundance, and 130 EV peptides (78 proteins) had a lower abundance in long-lived adults. Among longevity-associated peptides, 437 (58 proteins) were immune system related, and 12 (2 proteins) were muscle related. Using just three to five plasma EV peptides (mainly complement components C2-C6), we achieved high predictive accuracy for longevity (AUC range 0.91-1 in a hold-out validation dataset). Our findings suggest that immune cells produce longevity-associated plasma EVs and elucidate fundamental mechanisms regulating aging and longevity. EV longevity predictors suggest there may be merit in targeting complement pathways to extend lifespan, for instance, with any one of the multiple complement inhibitors currently available or in clinical development.
细胞外囊泡（EVs）在衰老过程中发挥着关键作用。在这项由美国国立衰老研究所资助的研究中，我们试图确定指示长寿的循环细胞外囊泡（EV）生物标志物。通过高分辨率质谱和流式细胞术分析了48名老年人（平均年龄77.2±1.7岁[范围72 - 80岁]；50%为女性，50%为黑人，50%生存时间<2年，50%生存时间≥10年）的血浆EV蛋白质组。利用受试者操作特征曲线下面积（AUCs）在发现数据集（n = 32）和验证数据集（n = 16）中评估EV肽预测长寿的能力。与长寿相关的大EV（LEV）血浆亚群主要与免疫细胞（HLA - ABC、CD9和CD31）和肌肉细胞（MCAD和RyR2）有关。在鉴定出的7960种血浆EV肽（519种蛋白质）中，46.4%与免疫系统相关，10.1%与肌肉相关。与短寿老年人相比，756种EV肽（131种蛋白质）在长寿成年人中丰度较高，130种EV肽（78种蛋白质）在长寿成年人中丰度较低。在与长寿相关的肽中，437种（58种蛋白质）与免疫系统相关，12种（2种蛋白质）与肌肉相关。仅使用三到五种血浆EV肽（主要是补体成分C2 - C6），我们就实现了对长寿的高预测准确性（在一个留出的验证数据集中AUC范围为$0.91 - 1$）。我们的研究结果表明免疫细胞产生与长寿相关的血浆EV，并阐明了调节衰老和长寿的基本机制。EV长寿预测指标表明，靶向补体途径以延长寿命可能具有价值，例如，使用目前可用的或正在临床开发的多种补体抑制剂中的任何一种。
