In the fourth episode of the Longevity & Aging Series, Dr. Carly Bobak from Dartmouth College, Dr. Cristian Coarfa from Baylor College of Medicine, and Dr. Andrew DiNardo from Baylor College of Medicine, discuss a research paper they co-authored that was published in Volume 14, Issue 5, of Aging (Aging-US), entitled, “Increased DNA methylation, cellular senescence and premature epigenetic aging in guinea pigs and humans with tuberculosis.”

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

Corresponding Authors - Carly A. Bobak - [email protected], Cristian Coarfa - [email protected], and Andrew R. DiNardo - [email protected]

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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Longevity & Aging Series

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Keywords - aging, tuberculosis, multi-cohort analysis, network analysis, DNA methylation, senescence, Cavia porcellus, DNA hypermethylation, epigenetic aging

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

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