Key processes characterizing human aging are immunosenescence and inflammaging. The capacity of the immune system to adequately respond to external perturbations (e.g., pathogens, injuries, and biochemical irritants) and to repair somatic mutations that may cause cancers or cellular senescence declines. An important goal remains to identify genetic or biochemical, predictive biomarkers for healthy aging. We recruited two cohorts in the age range 70 to 82, one afflicted by chronic illnesses (non-healthy aging, NHA) and the other in good health (healthy aging, HA). NHA criteria included major cardiovascular, neurodegenerative, and chronic pulmonary diseases, diabetes, and cancers. Quantitative analysis of forty proinflammatory cytokines in blood plasma and more than 500 proteins in urine was performed to identify candidate biomarkers for and biological pathway implications of healthy aging. Nine cytokines revealed lower quantities in blood plasma for the NHA compared with the HA groups (fold change > 1.5; p value < 0.025) including IL-12p40 and IL-12p70. We note that, sampling at two timepoints, intra-individual cytokine abundance patterns clustered in 86% of all 60 cases, indicative of person-specific, highly controlled multi-cytokine signatures in blood plasma. Twenty-three urinary proteins were differentially abundant (HA versus NHA; fold change > 1.5; p value < 0.01). Among the proteins increased in abundance in the HA cohort were glycoprotein MUC18, ephrin type-B receptor 4, matrix remodeling–associated protein 8, angiopoietin-related protein 2, K-cadherin, and plasma protease C1 inhibitor. These proteins have been linked to the extracellular matrix, cell adhesion, and vascular remodeling and repair processes. In silico network analysis identified the regulation of coagulation, antimicrobial humoral immune responses, and the IL-12 signaling pathway as enriched GO terms. To validate links of these preliminary biomarkers and IL-12 signaling with healthy aging, clinical studies using larger cohorts and functional characterization of the genes/proteins in cellular models of aging need to be conducted.

人类衰老的关键过程是免疫衰老和炎症。免疫系统对外部扰动（例如病原体、损伤和生化刺激物）做出充分反应以及修复可能导致癌症或细胞衰老的体细胞突变的能力下降。一个重要的目标仍然是确定健康衰老的遗传或生化预测生物标志物。我们招募了两组年龄在 70 至 82 岁之间的人群，一组患有慢性疾病（非健康老龄化，NHA），另一组健康状况良好（健康老龄化，HA）。NHA 标准包括主要心血管疾病、神经退行性疾病、慢性肺部疾病、糖尿病和癌症。对血浆中 40 种促炎细胞因子和尿液中 500 多种蛋白质进行定量分析，以确定健康衰老的候选生物标志物和生物途径影响。与 HA 组相比，NHA 组血浆中的九种细胞因子含量较低（倍数变化 > 1.5；p值 < 0.025），包括 IL-12p40 和 IL-12p70。我们注意到，在两个时间点采样，个体内细胞因子丰度模式聚集在所有 60 个病例中的 86%，表明血浆中存在个体特异性、高度受控的多细胞因子特征。23 种尿蛋白丰度存在差异（HA 与 NHA；倍数变化 > 1.5；p值 < 0.01）。HA 队列中丰度增加的蛋白质包括糖蛋白 MUC18、肝配蛋白 B 型受体 4、基质重塑相关蛋白 8、血管生成素相关蛋白 2、K-钙粘蛋白和血浆蛋白酶 C1 抑制剂。这些蛋白质与细胞外基质、细胞粘附以及血管重塑和修复过程有关。计算机网络分析将凝血调节、抗菌体液免疫反应和 IL-12 信号通路确定为丰富的 GO 术语。为了验证这些初步生物标志物和 IL-12 信号传导与健康衰老的联系，需要使用更大的队列进行临床研究，并对衰老细胞模型中的基因/蛋白质进行功能表征。