Health-related quality of life and DNA methylation-based aging biomarkers among survivors of childhood cancer

Abstract Background Childhood cancer survivors are at high risk for morbidity and mortality and poor patient-reported outcomes, typically health-related quality of life (HRQOL). However, associations between DNA methylation–based aging biomarkers and HRQOL have not been evaluated. Methods DNA methylation was generated with Infinium EPIC BeadChip on blood-derived DNA (median for age at blood draw = 34. 5 years, range = 18. 5-66. 6 years), and HRQOL was assessed with age at survey (mean = 32. 3 years, range = 18. 4-64. 5 years) from 2206 survivors in the St Jude Lifetime Cohort. DNA methylation–based aging biomarkers, including epigenetic age using multiple clocks (eg, GrimAge) and others (eg, DNAmB2M: beta-2-microglobulin; DNAmADM: adrenomedullin), were derived from the DNAm Age Calculator (https: //dnamage. genetics. ucla. edu). HRQOL was assessed using the Medical Outcomes Study 36-Item Short-Form Health Survey to capture 8 domains and physical and mental component summaries. General linear models evaluated associations between HRQOL and epigenetic age acceleration (EAA; eg, EAAGrimAge) or other age-adjusted DNA methylation–based biomarkers (eg, ageadjDNAmB2M) after adjusting for age at blood draw, sex, cancer treatments, and DNA methylation–based surrogate for smoking pack-years. All P values were 2-sided. Results Worse HRQOL was associated with greater EAAGrimAge (physical component summaries: β = -0. 18 years, 95% confidence interval CI = -0. 251 to -0. 11 years; P = 1. 85 × 10−5; and 4 individual HRQOL domains), followed by ageadjDNAmB2M (physical component summaries: β = -0. 08 years, 95% CI = -0. 124 to -0. 037 years; P =. 003; and 3 individual HRQOL domains) and ageadjDNAmADM (physical component summaries: β = -0. 082 years, 95% CI = -0. 125 to -0. 039 years; P =. 002; and 2 HRQOL domains). EAAHannum (Hannum clock) was not associated with any HRQOL. Conclusions Overall and domain-specific measures of HRQOL are associated with DNA methylation measures of biological aging. Future longitudinal studies should test biological aging as a potential mechanism underlying the association between poor HRQOL and increased risk of clinically assessed adverse health outcomes.