对人类整个生命周期外周血细胞进行多模式分析，揭示了衰老和长寿的独特免疫细胞特征。
Multi-modal profiling of peripheral blood cells across the human lifespan reveals distinct immune cell signatures of aging and longevity.
机构信息
Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, MA, USA.
Center for Regenerative Medicine (CReM), Boston University and Boston Medical Center, Boston, MA, USA.
出版信息
EBioMedicine. 2023 Apr;90:104514. doi: 10.1016/j.ebiom.2023.104514. Epub 2023 Mar 31.
BACKGROUND
Age-related changes in immune cell composition and functionality are associated with multimorbidity and mortality. However, many centenarians delay the onset of aging-related disease suggesting the presence of elite immunity that remains highly functional at extreme old age.
METHODS
To identify immune-specific patterns of aging and extreme human longevity, we analyzed novel single cell profiles from the peripheral blood mononuclear cells (PBMCs) of a random sample of 7 centenarians (mean age 106) and publicly available single cell RNA-sequencing (scRNA-seq) datasets that included an additional 7 centenarians as well as 52 people at younger ages (20-89 years).
FINDINGS
The analysis confirmed known shifts in the ratio of lymphocytes to myeloid cells, and noncytotoxic to cytotoxic cell distributions with aging, but also identified significant shifts from CD4 T cell to B cell populations in centenarians suggesting a history of exposure to natural and environmental immunogens. We validated several of these findings using flow cytometry analysis of the same samples. Our transcriptional analysis identified cell type signatures specific to exceptional longevity that included genes with age-related changes (e.g., increased expression of STK17A, a gene known to be involved in DNA damage response) as well as genes expressed uniquely in centenarians' PBMCs (e.g., S100A4, part of the S100 protein family studied in age-related disease and connected to longevity and metabolic regulation).
INTERPRETATION
Collectively, these data suggest that centenarians harbor unique, highly functional immune systems that have successfully adapted to a history of insults allowing for the achievement of exceptional longevity.
FUNDING
TK, SM, PS, GM, SA, TP are supported by NIH-NIAUH2AG064704 and U19AG023122. MM and PS are supported by NIHNIA Pepper center: P30 AG031679-10. This project is supported by the Flow Cytometry Core Facility at BUSM. FCCF is funded by the NIH Instrumentation grant: S10 OD021587.
背景
免疫细胞组成和功能的年龄相关变化与多种疾病和死亡率相关。然而，许多百岁老人延迟了与衰老相关疾病的发病，这表明存在精英免疫，在极端高龄时仍然具有高度功能性。
方法
为了确定免疫特异性衰老和人类极端长寿的模式，我们分析了来自 7 名百岁老人（平均年龄 106 岁）外周血单核细胞（PBMC）的新型单细胞图谱，以及公共单细胞 RNA 测序（scRNA-seq）数据集，其中包括另外 7 名百岁老人以及 52 名年龄较小的人（20-89 岁）。
发现
该分析证实了已知的随着年龄增长淋巴细胞与髓样细胞比例、非细胞毒性与细胞毒性细胞分布的变化，但也发现了百岁老人中 CD4 T 细胞向 B 细胞群体的显著转移，表明他们曾接触过天然和环境免疫原。我们使用相同样本的流式细胞术分析验证了其中的一些发现。我们的转录分析确定了与异常长寿相关的特定细胞类型特征，包括与年龄相关变化的基因（例如，参与 DNA 损伤反应的 STK17A 基因表达增加）以及仅在百岁老人 PBMC 中表达的基因（例如，S100A4，是 S100 蛋白家族的一部分，该家族在与年龄相关的疾病中进行了研究，与长寿和代谢调节有关）。
结论
总的来说，这些数据表明，百岁老人拥有独特的、高度功能性的免疫系统，成功地适应了过去的伤害，从而实现了异常长寿。
资助
TK、SM、PS、GM、SA、TP 得到 NIH-NIAUH2AG064704 和 U19AG023122 的支持。MM 和 PS 得到 NIH-NIA 胡椒中心：P30 AG031679-10 的支持。该项目得到 BUSM 流式细胞术核心设施的支持。FCCF 得到 NIH 仪器资助：S10 OD021587。
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