Increased DNA methylation, cellular senescence and premature epigenetic aging in guinea pigs and humans with tuberculosis.

IF 2.9 2区社会学 Q1 POLITICAL SCIENCE

Government and Opposition Pub Date : 2022-03-07 DOI:10.18632/aging.203936

Carly A Bobak, Abhimanyu, Harini Natarajan, Tanmay Gandhi, Sandra L Grimm, Tomoki Nishiguchi, Kent Koster, Santiago Carrero Longlax, Qiniso Dlamini, Jacquiline Kahari, Godwin Mtetwa, Jeffrey D Cirillo, James O'Malley, Jane E Hill, Cristian Coarfa, Andrew R DiNardo

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引用次数: 0

Abstract

Background: Tuberculosis (TB) is the archetypical chronic infection, with patients having months of symptoms before diagnosis. In the two years after successful therapy, survivors of TB have a three-fold increased risk of death.

Methods: Guinea pigs were infected with Mycobacterium tuberculosis (Mtb) for 45 days, followed by RRBS DNA methylation analysis. In humans, network analysis of differentially expressed genes across three TB cohorts were visualized at the pathway-level. Serum levels of inflammation were measured by ELISA. Horvath (DNA methylation) and RNA-seq biological clocks were used to investigate shifts in chronological age among humans with TB.

Results: Guinea pigs with TB demonstrated DNA hypermethylation and showed system-level similarity to humans with TB (p-value = 0.002). The transcriptome in TB in multiple cohorts was enriched for DNA methylation and cellular senescence. Senescence associated proteins CXCL9, CXCL10, and TNF were elevated in TB patients compared to healthy controls. Humans with TB demonstrate 12.7 years (95% CI: 7.5, 21.9) and 14.38 years (95% CI: 10.23-18.53) of cellular aging as measured by epigenetic and gene expression based cellular clocks, respectively.

Conclusions: In both guinea pigs and humans, TB perturbs epigenetic processes, promoting premature cellular aging and inflammation, a plausible means to explain the long-term detrimental health outcomes after TB.

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豚鼠和人类结核病患者的 DNA 甲基化增加、细胞衰老和表观遗传学过早衰老。

背景：肺结核（TB）是典型的慢性感染，患者在确诊前有数月的症状。在成功治疗后的两年内，结核病幸存者的死亡风险增加了三倍：方法：豚鼠感染结核分枝杆菌（Mtb）45 天，然后进行 RRBS DNA 甲基化分析。在人类中，对三个结核病队列的差异表达基因进行了通路级可视化网络分析。血清中的炎症水平是通过酶联免疫吸附试验测定的。利用 Horvath（DNA 甲基化）和 RNA-seq 生物钟研究了结核病患者的年龄变化：结果：豚鼠肺结核患者表现出 DNA 甲基化过高，与人类肺结核患者表现出系统水平的相似性（p 值 = 0.002）。多个队列中结核病的转录组富含 DNA 甲基化和细胞衰老。与健康对照组相比，结核病患者的衰老相关蛋白CXCL9、CXCL10和TNF升高。根据基于表观遗传学和基因表达的细胞时钟测量，结核病患者的细胞衰老时间分别为 12.7 年（95% CI：7.5-21.9 年）和 14.38 年（95% CI：10.23-18.53 年）：在豚鼠和人类中，结核病扰乱了表观遗传过程，促进了细胞过早衰老和炎症，这是解释结核病对健康造成长期不利影响的一种合理手段。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Government and Opposition POLITICAL SCIENCE-

CiteScore

6.70

自引率

10.70%

发文量

期刊介绍： Government and Opposition has been a leading international journal of comparative politics for over 40 years. Its distinctive voice amongst politics journals has ensured a large, worldwide circulation. Government and Opposition"s interests include: - developments in the theory and practice of democracy, including significant elections the evolution of political parties, and the consequences of new political challenges for governments and oppositions - the governance of the global economy and the implications of interdependence worldwide politics - including the politics of the European Union - major issues of public policy, especially from a comparative perspective theoretical and ethical dimensions of political issues and policy.