Research Paper|Volume 14, Issue 5|pp 2174—2193

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

Carly A. Bobak¹, Abhimanyu^2,^3,⁴, Harini Natarajan⁵, Tanmay Gandhi^6,⁷, Sandra L. Grimm^6,⁷, Tomoki Nishiguchi^2,^3,⁴, Kent Koster⁸, Santiago Carrero Longlax^2,^3,⁴, Qiniso Dlamini⁹, Jacquiline Kahari⁹, Godwin Mtetwa⁹, Jeffrey D. Cirillo⁸, James O’Malley^1,¹⁰, Jane E. Hill¹¹, Cristian Coarfa^6,⁷, Andrew R. DiNardo^2,^3,⁴

¹Biomedical Data Science, Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA
²The Global Tuberculosis Program, Baylor College of Medicine, Houston, TX 77030, USA
³William Shearer Center for Human Immunobiology, Texas Children's Hospital, Houston, TX 77030, USA
⁴Immigrant and Global Health, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
⁵Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Dartmouth College, Hanover, NH 03755, USA
⁶Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
⁷Molecular and Cellular Biology Department, Baylor College of Medicine, Houston, TX 77030, USA
⁸Department of Microbial Pathogenesis and Immunology, Texas A&M University Health, Bryan, TX 77807, USA
⁹Baylor-Swaziland Children’s Foundation, Mbabane, Swaziland
¹⁰The Dartmouth Institute, Dartmouth College, Hanover, NH 03755, USA
¹¹Department of Chemical and Biological Engineering, University of British Columbia, Vancouver, BC, Canada

* Co-first authors contributing equally

# Co-senior authors contributing equally

Received: December 23, 2021Accepted: February 22, 2022Published: March 7, 2022

https://doi.org/10.18632/aging.203936

Copyright: © 2022 Bobak et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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.