Epigenetic clocks, which measure DNA methylation status at specific sites across the genome, have emerged as reliable estimators of biological age, and certain clocks may be able to predict the risk of developing cancer as well as cancer-related death.1,2

In a new study published in Cancer, an epigenetic clock showed that treatment for patients with head and neck cancer was associated with epigenetic age acceleration, defined as having a DNA methylation age that is older than the person’s chronological age.3

Furthermore, the epigenetic age acceleration was linked to increases in inflammatory molecules and patient-reported fatigue. These findings suggest that epigenetic clocks may provide an objective approach for evaluating and monitoring fatigue, according to researchers.

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“Our study is among the first to explore the association of epigenetic age acceleration and inflammation and fatigue among cancer patients,” said lead study author Canhua Xiao, PhD, RN, an associate professor at Emory University School of Nursing in Atlanta.

Study Rationale and Details

Research has shown that nearly all patients with head and neck cancer experience fatigue after radiation and chemotherapy, and that fatigue can last up to 2 years after treatment.4

Dr Xiao and colleagues had previously observed a strong association between greater fatigue and increased inflammation, but the biological processes underpinning these changes and the role that DNA methylation may play were unknown.

With that in mind, the researchers conducted a study of 133 patients with head and neck cancer and no distant metastases. Most of the patients were men (72%) and White (82%), and about half of the cancers (53%) were related to HPV infection.

All patients received radiotherapy. Most received concurrent chemotherapy (80%), and 41% underwent surgery about 1 month before starting radiotherapy.

The researchers evaluated epigenetic age acceleration, fatigue, and inflammation at 4 time points: prior to radiotherapy, immediately after radiotherapy, 6 months after completing radiotherapy, and 12 months after completion.

Epigenetic age acceleration was calculated using the epigenetic clock DNAm PhenoAge. Patients’ fatigue levels were assessed using the Multidimensional Fatigue Inventory (MFI-20) questionnaire, and inflammation was assessed by measuring levels of inflammatory markers in the plasma.

Results showed that the greatest increase in epigenetic age acceleration occurred immediately after radiotherapy. It was 4.9 years higher, on average, immediately after radiotherapy, compared with before radiotherapy (P <.001). There was no significant increase in epigenetic age acceleration at 6 months and 12 months after radiotherapy.

The researchers also found a significant increase in epigenetic age acceleration (4.7 years) at the end of treatment for patients who received chemotherapy, compared with patients who did not (P =.001).

Half of patients reported having severe fatigue at some point during the study, especially right after treatment. These patients had significantly greater epigenetic age acceleration — 3.1 years higher, on average — compared with patients who had low fatigue.

The increase in epigenetic age acceleration was even more pronounced among patients who had severe fatigue and did not have HPV-related tumors — 5.6 years higher, on average, 12 months after treatment completion.

The study also showed a strong association between epigenetic age acceleration and elevated levels of inflammatory markers, particularly C-reactive protein (CRP) and interleukin-6 (IL-6).

Epigenetic age acceleration over time was 4.6 years higher for patients with high CRP levels and 5.9 years higher for patients with high IL-6 levels, compared with patients who had low levels of these markers (P <.001).  

The researchers found that levels of CRP, IL-6, and IL-1 receptor antagonist accounted for the association they saw between epigenetic age acceleration and fatigue.