Causes of Immune Cell Senescence in Aging Humans

细胞衰老是哺乳动物细胞对细胞作出反应时遇到的一种稳定的增殖停滞 外在和内在的应激，如端粒功能障碍。在哺乳动物中，这种应激反应不仅 具有抑制癌症发展的功能，但在组织修复和胚胎发育过程中也发挥着重要作用 发展。因此，细胞衰老的进化使机体受益。衰老的持久力 然而，组织中的细胞也对健康和健身有很大的负面影响。例如，衰老 随着年龄的增长，细胞在各种哺乳动物组织中积累，这种衰老细胞的积累 最近被证明是衰老和与年龄相关的发展的一个主要因素 小鼠的病理学。然而，与衰老相关的细胞积累是令人惊讶的，因为 在不同的条件下，它们可以通过先天和获得性免疫反应有效地从组织中清除。 幼年动物的环境，例如在组织修复期间，以及在胚胎和癌症期间 发展。一个模型可以解释为什么衰老细胞随着年龄的增长而积累 哺乳动物的组织是免疫细胞本身随着我们年龄的增长而日益衰老，从而 日益减弱的免疫反应，否则将清除衰老组织中的衰老细胞。 这一提议检验了这样一个假设，即衰老导致人类循环免疫细胞的各个亚群 随着年龄的增长，越来越多地经历端粒功能障碍导致的细胞衰老，从而导致 与年龄相关的免疫细胞功能的全面丧失。使用一种新技术通过以下方式检测衰老细胞 流式细胞术，我们建议用来鉴定人类外周血单核细胞的特定群体 (外周血单核细胞)，随着年龄的增长而逐渐经历细胞衰老。此外，我们还将描述 RNA-seq和ATAC-seq分别检测衰老PBMCs的转录组和表观基因组 更好地定义特定PBMC群体的衰老状态，同时也发现潜在的目标 调节人外周血单核细胞衰老反应的治疗干预。最后，使用 免疫荧光分析和体外培养人外周血单个核细胞，我们将揭示其原因和功能 人类外周血单核细胞衰老的后果和抑制它们的测试策略，总体目标是 延缓免疫细胞衰老，改善免疫功能，抑制年龄相关疾病。

Cellular senescence is a stable proliferative arrest that is encountered by mammalian cells in response to cell extrinsic and intrinsic stresses, such as telomere dysfunction. In mammals, this stress response not only functions to suppress cancer development, but it also plays important roles during tissue repair and embryonic development. Cellular senescence, therefore, evolved to benefit the organism. The persistence of senescent cells in tissue, however, also has a substantial negative impact on health and fitness. For example, senescent cells accumulate with advancing age in various mammalian tissues and this accumulation of senescent cells has recently been show to be a major contributing factor to aging and the development of age-associated pathologies in mice. The aging-associated accumulation of senescent cells, however, is surprising, given that they can be efficiently cleared from tissue by innate and adapted immune responses under different circumstances in young animals, such as during tissue repair, as well as during embryonic and cancer development. One model that could explain why senescent cells accumulate with advancing age in mammalian tissue is that immune cells themselves increasingly become senescent as we age, thereby increasingly weakening immune responses that would otherwise clear senescent cells from aged tissue. This proposal tests the hypothesis that aging causes various subsets of human circulating immune cells to increasingly undergo telomere dysfunction-induced cellular senescence with advancing age, thereby resulting in an age-associated overall loss of immune cell function. Using a novel technique to detect senescent cells by flow cytometry, we propose to identify specific populations of human peripheral blood mononuclear cells (PBMCs) that increasingly undergo cellular senescence with advancing age. Additionally, we will characterize the transcriptome and epigenome of senescent PBMCs by RNA-seq and ATAC seq, respectively, not only to better define the senescence state of specific PBMC populations, but also to uncover potential targets for therapeutic interventions to modulate senescence responses of human PBMCs. Lastly, using immunofluorescence analysis and ex-vivo cultures of human PBMCs, we will reveal the causes and functional consequences of PBMC senescence in humans and test strategies to suppress them, with the overall goal of reducing immune cell senescence, improving immune function, and suppressing age-associated diseases.