Epigenetic Age Acceleration Mediates Treatment Effects on Cardiometabolic and Cardiovascular Risk in Childhood Cancer Survivors

Authors

Xiaoxi Meng
Tiffany Eulalio
Yoonji Kim
John Easton
Heather L Mulder
Emily Walker
Geoffrey Neale
Nan Song
Kyla Shelton
Rebecca M Howell
Mengqi Xing
Sedigheh Mirzaei
Deo Kumar Srivastava
Bonnie Ky
Stephanie B Dixon
Melissa M Hudson
Kirsten K Ness
Gregory T Armstrong
Zhaoming Wang

Language

English

Publication Date

10-1-2025

Journal

JACC: CardioOncology

PMID

40624951

PMCID

PMC12790056

PubMedCentral® Posted Date

6-21-2025

PubMedCentral® Full Text Version

Post-print

Abstract

BACKGROUND: Childhood cancer survivors are at increased risk for epigenetic age acceleration (EAA) and subsequent morbidities, including cardiometabolic risk factors (CMRFs) and cardiovascular diseases, because of prior genotoxic treatments.

OBJECTIVES: The aim of this study was to evaluate the mediating role of EAA in the relationship between cancer treatment exposures and risk for CMRFs and cardiovascular diseases.

METHODS: This study included 2,939 5-year survivors from SJLIFE (St. Jude Lifetime Cohort) who underwent DNA methylation profiling using peripheral blood mononuclear cells. EAA was calculated using 3 established epigenetic clocks: DunedinPACE, PCPhenoAge, and GrimAge2. Treatment data, including body region-specific radiotherapy (RT) and chemotherapeutic agents such as anthracyclines and corticosteroids, were abstracted from medical records. Outcomes included 3 CMRFs (abnormal glucose metabolism, hypertension, and obesity) and 2 cardiovascular diseases (cardiomyopathy and myocardial infarction). Mediation analysis was conducted to quantify the extent to which EAA mediated the association between each treatment exposure and each clinical outcome.

RESULTS: EAA partially mediated the associations between abdominal RT and abnormal glucose metabolism (DunedinPACE 35.4%, GrimAge2 16.2%), between abdominal RT (DunedinPACE 25.9%) or anthracyclines (DunedinPACE 12.5%) and hypertension, and between corticosteroids and obesity (DunedinPACE 8.6%). EAA also mediated the associations between heart RT and cardiomyopathy (PCPhenoAge 30.3%, DunedinPACE 19.9%, GrimAge2 14.4%) and myocardial infarction (PCPhenoAge 24.1%, DunedinPACE 15.5%, GrimAge2 13.2%), and anthracyclines and cardiomyopathy (GrimAge2 6.0%, PCPhenoAge 5.2%, DunedinPACE 3.9%).

CONCLUSIONS: EAA accounted for a substantial proportion of the association between cancer treatment exposures and risk for CMRFs and cardiovascular diseases. These findings provide insight into biological aging as a potential mechanistic pathway and support the development of interventions targeting accelerated aging to mitigate long-term treatment-related toxicities and reduce premature mortality in this high-risk population.

Keywords

biomarkers, cancer survivorship, cancer treatment, cardiometabolic risk factors, cardiovascular diseases, childhood cancer survivor, epidemiology, epigenetic age acceleration, epigenetics, mediation, prevention, treatment

Published Open-Access

yes

Recommended Citation

Meng, Xiaoxi; Eulalio, Tiffany; Kim, Yoonji; et al., "Epigenetic Age Acceleration Mediates Treatment Effects on Cardiometabolic and Cardiovascular Risk in Childhood Cancer Survivors" (2025). Faculty, Staff and Student Publications. 5863.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5863