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Patients who underwent radiotherapy for head and neck cancer experienced accelerated biological aging, which contributed to fatigue and inflammation, a prospective longitudinal study found.

Changes in epigenetic age acceleration (EAA) were significant over time, with the biggest increase -- 4.9 years -- seen immediately after the completion of radiotherapy (P<0.001), reported Canhua Xiao, RN, PhD, of Emory University School of Nursing in Atlanta, and colleagues.

The study also demonstrated that EAA was associated with greater inflammation and fatigue, even up to a year after treatment, they noted in .

While chronological age is a strong risk factor for chronic health problems, Xiao and colleagues said that it often differs from epigenetic age and may be a limited predictor of age-associated disorders. On the other hand, they noted that epigenetic clocks, based on blood DNA methylation measures, have become reliable aging biomarkers.

"Importantly, acceleration of epigenetic age, which is the discordance between epigenetic and chronological age, can be used to quantify the age acceleration process, which most current age markers or chronological age cannot," they wrote.

Xiao's group evaluated EAA in patients with head and neck cancer who underwent radiotherapy with or without chemotherapy, as well as the relationship of EAA with fatigue and inflammation before radiotherapy and up to 1 year after radiotherapy.

The study included 133 patients enrolled at oncology clinics at Emory University's Winship Cancer Institute. Most patients were men (72%) and white (82%), with a mean age of 59 years. Fifty-four percent were diagnosed with oropharyngeal cancer; of these, 90% were human papillomavirus (HPV)-related cancers. All had advanced disease and underwent radiotherapy; 80% underwent concurrent chemotherapy.

Data were collected at four time points -- before radiotherapy, immediately after completing radiotherapy, 6 months after radiotherapy, and 12 months after radiotherapy.

EAA was calculated using the Levine epigenetic clock (DNAm PhenoAge), adjusted for chronological age, while fatigue was measured with the Multidimensional Fatigue Inventory-20 questionnaire. Inflammation was measured using standard laboratory techniques.

Xiao and colleagues found that the magnitude of age acceleration gradually decreased after radiotherapy, with a nonsignificant increase of 0.3 years in EAA persisting 1 year after the completion of treatment (P=0.61) compared with baseline. Post-hoc analyses showed a significant increase in EAA -- 4.7 years -- at the end of radiotherapy among those who also received chemotherapy, but not those who did not receive chemotherapy (P=0.001).

In addition, fatigue scores increased from baseline to the end of radiotherapy, and then gradually decreased over time. Over the course of the study, patients with severe fatigue experienced 3.1 years higher EAA compared with those who reported low fatigue (P<0.001).

EAA was most prominent in patients with HPV-unrelated disease at 12 months after treatment, the authors noted; those with HPV-unrelated tumors who experienced severe fatigue showed an increase of 5.63 years in EAA compared with those who reported low fatigue (P=0.018).

The study also showed that EAA was positively associated with several inflammatory markers over time. For example, patients who had high C-reactive protein levels had an EAA increase of 4.6 years, while those with high levels of interleukin-6 had an increase of 5.9 years, compared with patients who had low levels. Further analysis showed that inflammatory markers significantly mediated the relationship between EAA and fatigue.

The findings "add to the body of evidence suggesting that long-term toxicity and possibly increased mortality incurred from chemoradiation for patients with [head and neck cancer] may be related to increased EAA and its association with inflammation," the authors concluded. "Interventional studies to reduce inflammation, including before chemoradiation, might significantly benefit patients who have cancer in decelerating the aging process and subsequently reducing age-related chronic health problems such as fatigue."

In an , Kord Kober, PhD, and Sue Yom, MD, PhD, both of the University of California San Francisco, noted that cancer-related fatigue may not be just an ancillary symptom, "but a meaningful physiological phenomenon reflecting a dangerous biology at work in these patients." They further speculated that a chronic inflammatory state that predisposes patients to fatigue and premature aging could be a contributing factor to poor outcomes.

"If there are possibilities that we might be able to combine advances in oncologic aims with improving the overall health and quality of life of our patients who are at highest risk in all of these domains, these deserve concentrated and serious exploration," they wrote.

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