Increased DNA Methylation, Cellular Senescence and Premature Epigenetic Aging in Guinea Pigs and Humans With Tuberculosis

Authors

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

Publication Date

3-7-2022

Journal

Aging

DOI

10.18632/aging.203936

PMID

35256539

PMCID

PMC8954968

PubMedCentral® Posted Date

3-7-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Cellular Senescence, DNA Methylation, Epigenesis, Genetic, Guinea Pigs, Humans, Inflammation, Tuberculosis, tuberculosis, multi-cohort analysis, network analysis, DNA methylation, Cavia porcellus, senescence, DNA hypermethylation, epigenetic aging

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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