Epigenetic age acceleration, fatigue, and inflammation in patients undergoing radiation therapy for head and neck cancer: A longitudinal study.
Level 3 - non-randomized controlled study
Prospective longitudinal cohort study assessing biomarkers and clinical outcomes over time without an unexposed control group
PubMed 34027995 · doi:10.1002/cncr.33641
What was done
A prospective longitudinal study followed 133 patients with non-metastatic head and neck cancer undergoing radiotherapy (mostly concurrent chemoradiation). Patients were evaluated before radiotherapy, immediately after treatment, and at 6 and 12 months post-radiotherapy. Epigenetic age acceleration (EAA) was calculated from blood DNA methylation (Illumina MethylationEPIC BeadChip) using the Levine DNAmPhenoAge clock adjusted for chronological age. Fatigue was assessed using the Multidimensional Fatigue Inventory-20, and circulating inflammatory markers (CRP and IL-6) were measured.
What was found
EAA increased significantly over time, with the largest increase of 4.9 years observed immediately after radiotherapy (P < .001). Increased EAA was associated with elevated fatigue over time (P = .003). Patients with severe fatigue exhibited 3.1 years higher EAA than those with low fatigue (P < .001), reaching 5.6 years higher (P = .018) in patients with HPV-unrelated disease at 12 months post-treatment. EAA was positively associated with CRP and IL-6 (P < .001); high CRP and IL-6 levels were associated with 4.6- and 5.9-year increases in EAA, respectively (P < .001). Both CRP (95% CI, 0.060-0.279) and IL-6 (95% CI, 0.024-0.220) statistically mediated the association between EAA and fatigue.
Why it matters
This study provides evidence that cancer therapy accelerates biological aging in tandem with systemic inflammation, identifying a potential biological pathway underlying cancer-related fatigue.
Limits
The study lacked an unexposed or non-cancer control group. The cohort was predominantly male, White, and had advanced disease receiving concurrent chemotherapy, which may confound the isolated effect of radiation. Statistical mediation cannot establish definitive mechanistic causality.
Cited by
- supports Head and neck cancer patients treated with chemo-radiotherapy experienced an immediate 4.9-year acceleration in epigenetic age that normalized back to baseline after six to twelve months.
- supports Epigenetic age acceleration following cancer treatment correlated with inflammatory biomarkers, and patients with high inflammatory biomarkers at one year sustained epigenetic age acceleration.