The senescence-associated secretome as an indicator of age and medical risk
The senescence-associated secretome as an indicator of age and medical risk
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DOI：
10.1172/jci.insight.133668
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发表时间：
2020-06-18
期刊：
影响因子：
8
通讯作者：
LeBrasseur, Nathan K.
中科院分区：
文献类型：
--
作者：
Schafer, Marissa J.;Zhang, Xu;LeBrasseur, Nathan K.
由衰老细胞产生的衰老相关分泌表型(SASP)是年龄相关功能障碍的潜在驱动因素。我们测试了循环中的SASP蛋白浓度是否反映了人类的年龄和医疗风险。我们首先筛选了衰老的内皮细胞、成纤维细胞、前脂肪细胞、上皮细胞和成肌细胞，以确定人类特征的候选细胞。然后，我们测试了循环SASP蛋白和来自整个生命周期的个体和接受手术治疗流行但不同的年龄相关疾病的老年人的临床数据之间的相关性。以社区为基础的20-90岁人群样本(回溯性横断面)被研究以检验循环SASP因素和实际年龄之间的关联。对年龄在60-90岁之间的人群和分别接受严重主动脉狭窄(前瞻性纵向)或卵巢癌(前瞻性病例对照)手术的老年人进行了研究，以评估循环中SASP蛋白浓度与生物学年龄(由年龄相关健康缺陷的累积决定)和/或手术后结果之间的关系。我们发现SASP蛋白与年龄、身体虚弱和术后不良结局呈正相关。由生长分化因子15(GDF15)、肿瘤坏死因子受体超家族成员6(Fas)、骨桥蛋白(OPN)、肿瘤坏死因子受体1(TNFR1)、激活素A、趋化因子(C-C基序)配体3(CCL3)和IL-15组成的7个SASP因子对不良事件的预测明显优于单一SASP蛋白或年龄。我们的研究结果表明，循环SASP可能是临床上有用的年龄相关健康的候选生物标志物，也是介入人类研究的有力工具。
Produced by senescent cells, the senescence-associated secretory phenotype (SASP) is a potential driver of age-related dysfunction. We tested whether circulating concentrations of SASP proteins reflect age and medical risk in humans. We first screened senescent endothelial cells, fibroblasts, preadipocytes, epithelial cells, and myoblasts to identify candidates for human profiling. We then tested associations between circulating SASP proteins and clinical data from individuals throughout the life span and older adults undergoing surgery for prevalent but distinct age-related diseases. A community-based sample of people aged 20-90 years (retrospective cross-sectional) was studied to test associations between circulating SASP factors and chronological age. A subset of this cohort aged 60-90 years and separate cohorts of older adults undergoing surgery for severe aortic stenosis (prospective longitudinal) or ovarian cancer (prospective case-control) were studied to assess relationships between circulating concentrations of SASP proteins and biological age (determined by the accumulation of age-related health deficits) and/or postsurgical outcomes. We showed that SASP proteins were positively associated with age, frailty, and adverse postsurgery outcomes. A panel of 7 SASP factors composed of growth differentiation factor 15 (GDF15), TNF receptor superfamily member 6 (FAS), osteopontin (OPN), TNF receptor 1 (TNFR1), ACTIVIN A, chemokine (C-C motif) ligand 3 (CCL3), and IL-15 predicted adverse events markedly better than a single SASP protein or age. Our findings suggest that the circulating SASP may serve as a clinically useful candidate biomarker of age-related health and a powerful tool for interventional human studies.