Epigenetic age acceleration is associated with occupational exposures, sex, and survival in amyotrophic lateral sclerosisResearch in context

Yue Zhao; Xiayan Li; Kai Wang; Gayatri Iyer; Stacey A. Sakowski; Lili Zhao; Samuel Teener; Kelly M. Bakulski; John F. Dou; Bryan J. Traynor; Alla Karnovsky; Stuart A. Batterman; Eva L. Feldman; Maureen A. Sartor; Stephen A. Goutman

EBioMedicine (Nov 2024)

Epigenetic age acceleration is associated with occupational exposures, sex, and survival in amyotrophic lateral sclerosisResearch in context

Yue Zhao,
Xiayan Li,
Kai Wang,
Gayatri Iyer,
Stacey A. Sakowski,
Lili Zhao,
Samuel Teener,
Kelly M. Bakulski,
John F. Dou,
Bryan J. Traynor,
Alla Karnovsky,
Stuart A. Batterman,
Eva L. Feldman,
Maureen A. Sartor,
Stephen A. Goutman

Affiliations

Yue Zhao: Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA
Xiayan Li: Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA
Kai Wang: Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA
Gayatri Iyer: Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA
Stacey A. Sakowski: Department of Neurology, University of Michigan, Ann Arbor, MI, USA; NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI, USA
Lili Zhao: Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA
Samuel Teener: NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI, USA
Kelly M. Bakulski: Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA
John F. Dou: Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA
Bryan J. Traynor: Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA
Alla Karnovsky: Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA
Stuart A. Batterman: Environmental Health Sciences, University of Michigan, Ann Arbor, MI, USA
Eva L. Feldman: Department of Neurology, University of Michigan, Ann Arbor, MI, USA; NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI, USA
Maureen A. Sartor: Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA; Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA; Corresponding author. Department of Computational Medicine and Bioinformatics, 100 Washtenaw Ave., Ann Arbor, MI, 48109, USA.
Stephen A. Goutman: Department of Neurology, University of Michigan, Ann Arbor, MI, USA; NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI, USA; Corresponding author. Department of Neurology, 1500 E Medical Center Dr, Ann Arbor, MI, 48109-2200, USA.

Journal volume & issue: Vol. 109
p. 105383

Abstract

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Summary: Background: Amyotrophic lateral sclerosis (ALS) is linked to ageing and genetic and environmental risk factors, yet underlying mechanisms are incompletely understood. We aimed to evaluate epigenetic age acceleration (EAA), i.e., DNA methylation (DNAm) age acceleration, and its association with ALS case status and survival. Methods: In this study, we included 428 ALS and 288 control samples collected between 2011 and 2021. We calculated EAA using the GrimAge residual method from ALS and control blood samples and grouped participants with ALS into three ageing groups (fast, normal, slow). We associated EAA with ALS case status and survival, stratified by sex, and correlated it with environmental and biological factors through occupational exposure assessments, immune cell proportions, and transcriptome changes. Findings: Participants with ALS had higher average EAA by 1.80 ± 0.30 years (p < 0.0001) versus controls. Participants with ALS in the fast ageing group had a hazard ratio of 1.52 (95% confidence interval 1.16–2.00, p = 0.0028) referenced to the normal ageing group. In males, this hazard ratio was 1.55 (95% confidence interval 1.11–2.17, p = 0.010), and EAA was positively correlated with high-risk occupational exposures including particulate matter (adj.p < 0.0001) and metals (adj.p = 0.0087). Also, in male participants with ALS, EAA was positively correlated with neutrophil proportions and was negatively correlated with CD4+ T cell proportions. Pathways dysregulated in participants with ALS with fast ageing included spliceosome, nucleocytoplasmic transport, axon guidance, and interferons. Interpretation: EAA was associated with ALS case status and, at least in males, with shorter survival after diagnosis. The effect of EAA on ALS was partially explained by occupational exposures and immune cell proportions in a sex-dependent manner. These findings highlight the complex interactions of ageing and exposures in ALS. Funding: NIH, CDC/National ALS Registry, ALS Association, Dr. Randall Whitcomb Fund for ALS Genetics, Peter Clark Fund for ALS Research, Sinai Medical Staff Foundation, Scott L. Pranger ALS Clinic Fund, NeuroNetwork Therapeutic Discovery Fund, NeuroNetwork for Emerging Therapies.

Published in EBioMedicine

ISSN: 2352-3964 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General)
Website: http://www.journals.elsevier.com/ebiomedicine/

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