Reed Eric R, Chandler Kevin B, Lopez Prisma, Costello Catherine E, Andersen Stacy L, Perls Thomas T, Li Mengze, Bae Harold, Soerensen Mette, Monti Stefano, Sebastiani Paola
Data Intensive Study Center, Tufts University, Boston, MA, USA.
Center for Biomedical Mass Spectrometry, Department of Biochemistry and Cell Biology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
Geroscience. 2025 Feb;47(1):1199-1220. doi: 10.1007/s11357-024-01286-x. Epub 2024 Jul 25.
In previous work, we used a SomaLogic platform targeting approximately 5000 proteins to generate a serum protein signature of centenarians that we validated in independent studies that used the same technology. We set here to validate and possibly expand the results by profiling the serum proteome of a subset of individuals included in the original study using liquid chromatography tandem mass spectrometry (LC-MS/MS). Following pre-processing, the LC-MS/MS data provided quantification of 398 proteins, with only 266 proteins shared by both platforms. At 1% FDR statistical significance threshold, the analysis of LC-MS/MS data detected 44 proteins associated with extreme old age, including 23 of the original analysis. To identify proteins for which associations between expression and extreme-old age were conserved across platforms, we performed inter-study conservation testing of the 266 proteins quantified by both platforms using a method that accounts for the correlation between the results. From these tests, a total of 80 proteins reached 5% FDR statistical significance, and 26 of these proteins had concordant pattern of gene expression in whole blood generated in an independent set. This signature of 80 proteins points to blood coagulation, IGF signaling, extracellular matrix (ECM) organization, and complement cascade as important pathways whose protein level changes provide evidence for age-related adjustments that distinguish centenarians from younger individuals. The comparison with blood transcriptomics also highlights a possible role for neutrophil degranulation in aging.
在之前的研究中，我们使用了一个针对约5000种蛋白质的SomaLogic平台，生成了百岁老人的血清蛋白质特征，我们在使用相同技术的独立研究中对其进行了验证。我们在此通过使用液相色谱串联质谱法（LC-MS/MS）分析原始研究中一部分个体的血清蛋白质组，来验证并可能扩展这些结果。经过预处理后，LC-MS/MS数据提供了398种蛋白质的定量信息，两个平台仅共享266种蛋白质。在1%的错误发现率（FDR）统计显著性阈值下，对LC-MS/MS数据的分析检测到44种与高龄相关的蛋白质，其中包括原始分析中的23种。为了确定在不同平台上表达与高龄之间的关联均保持一致的蛋白质，我们使用一种考虑结果间相关性的方法，对两个平台都定量的266种蛋白质进行了研究间一致性测试。从这些测试中，共有80种蛋白质达到了5%的FDR统计显著性，其中26种蛋白质在独立样本中生成的全血中具有一致的基因表达模式。这80种蛋白质的特征表明，凝血、胰岛素样生长因子（IGF）信号传导、细胞外基质（ECM）组织和补体级联是重要的途径，其蛋白质水平的变化为区分百岁老人与年轻人的年龄相关调整提供了证据。与血液转录组学的比较还突出了中性粒细胞脱颗粒在衰老中的可能作用。
