The authors measured epigenetic age acceleration (EAA) during and after cancer treatment and its association with inflammation and fatigue, which is a debilitating symptom in patients with cancer.

Patients who had head and neck cancer without distant metastases were assessed before, immediately after, and at 6 months and 12 months postradiotherapy. Blood DNA methylation was assessed using a proprietary bead chip (the Illumina MethylationEPIC BeadChip). EAA was calculated using the Levine epigenetic clock (DNAmPhenoAge), adjusted for chronological age. Fatigue was assessed using the Multidimensional Fatigue Inventory‐20. Inflammatory markers were measured using standard techniques.

Most patients (N = 133) were men, White, had advanced disease, and received concurrent chemoradiation. EAA changes over time were significant, with the largest increase (4.9 years) observed immediately after radiotherapy (P < .001). Increased EAA was associated with elevated fatigue (P = .003) over time, and patients who had severe fatigue experienced 3.1 years higher EAA than those who had low fatigue (P < .001), which was more prominent (5.6 years; P = .018) for patients who had human papillomavirus‐unrelated disease at 12 months posttreatment. EAA was also positively associated with inflammatory markers, including C‐reactive protein (CRP) and interleukin‐6 (IL‐6), over time (P < .001), and patients who had high CRP and IL‐6 levels exhibited increases of 4.6 and 5.9 years, respectively, in EAA compared with those who had low CRP and IL‐6 levels (P < .001). CRP and IL‐6 mediated the association between EAA and fatigue (CRP: 95% CI, 0.060‐0.279; IL‐6: 95% CI, 0.024‐0.220).

Patients with head and neck cancer experienced increased EAA, especially immediately after treatment completion. EAA was associated with greater fatigue and inflammation, including 1 year after treatment. Inflammation may be a target to reduce the impact of age acceleration on poor functional outcomes.