Center for Cell Signaling, Rutgers-New Jersey Medical School, Rutgers Biomedical and Health Sciences, Rutgers University, Newark, New Jersey, USA.
Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers-New Jersey Medical School, Rutgers Biomedical and Health Sciences, Rutgers University, Newark, New Jersey, USA.
Aging Cell. 2021 May;20(5):e13344. doi: 10.1111/acel.13344. Epub 2021 May 3.
Aging leads to a progressive functional decline of the immune system, rendering the elderly increasingly susceptible to disease and infection. The degree to which immune cell senescence contributes to this decline remains unclear, however, since markers that label immune cells with classical features of cellular senescence accurately and comprehensively have not been identified. Using a second-generation fluorogenic substrate for β-galactosidase and multi-parameter flow cytometry, we demonstrate here that peripheral blood mononuclear cells (PBMCs) isolated from healthy humans increasingly display cells with high senescence-associated β-galactosidase (SA-βGal) activity with advancing donor age. The greatest age-associated increases were observed in CD8+ T-cell populations, in which the fraction of cells with high SA-βGal activity reached average levels of 64% in donors in their 60s. CD8+ T cells with high SA-βGal activity, but not those with low SA-βGal activity, were found to exhibit features of telomere dysfunction-induced senescence and p16-mediated senescence, were impaired in their ability to proliferate, developed in various T-cell differentiation states, and had a gene expression signature consistent with the senescence state previously observed in human fibroblasts. Based on these results, we propose that senescent CD8+ T cells with classical features of cellular senescence accumulate to levels that are significantly higher than previously reported and additionally provide a simple yet robust method for the isolation and characterization of senescent CD8+ T cells with predictive potential for biological age.
衰老是导致免疫系统功能逐渐下降的原因，使老年人更容易患病和感染。然而，由于尚未确定能够准确和全面地标记具有细胞衰老经典特征的免疫细胞的标志物，因此免疫细胞衰老在这种下降中所起的作用程度仍不清楚。在这里，我们使用第二代β-半乳糖苷酶荧光底物和多参数流式细胞术，证明了从健康人类中分离出的外周血单核细胞（PBMC）随着供体年龄的增长，越来越多地显示出具有高衰老相关β-半乳糖苷酶（SA-βGal）活性的细胞。在 CD8+T 细胞群体中观察到最大的年龄相关增加，其中具有高 SA-βGal 活性的细胞分数在 60 多岁的供体中达到平均水平的 64%。具有高 SA-βGal 活性的 CD8+T 细胞，而不是具有低 SA-βGal 活性的细胞，表现出端粒功能障碍诱导的衰老和 p16 介导的衰老的特征，其增殖能力受损，在各种 T 细胞分化状态下发育，并具有与先前在人类成纤维细胞中观察到的衰老状态一致的基因表达特征。基于这些结果，我们提出具有细胞衰老经典特征的衰老 CD8+T 细胞积累到显著高于先前报道的水平，并且还提供了一种简单但强大的方法来分离和表征具有预测生物年龄潜力的衰老 CD8+T 细胞。
