Chronic fatigue and inflammation are debilitating symptoms in patients with cancer. Anti-cancer therapies may alter epigenetic signatures on the DNA contributing to an acceleration of biological processes of aging, greater inflammation and fatigue, a new study finds.

“Your biological age or the epigenetic age might be different from your chronological age. If your epigenetic age is older than your chronological age, you might age faster, [and be more susceptible to] age-associated adverse conditions.  If your epigenetic age is younger than your chronological age, you might age slower,” explains Canhua Xiao, PhD, RN, FAAN, of the Emory University School of Nursing, in Atlanta.

Canhua Xiao, PhD, RN, FAAN, of the Emory University School of Nursing, in Atlanta

The findings are published in the article “Epigenetic age acceleration, fatigue, and inflammation in patients undergoing radiation therapy for head and neck cancer: A longitudinal study” in Cancer, the journal of the American Cancer Society.

One of the epigenetic signatures alters DNA by appending methyl groups to the code. Usually, methylation occurs on DNA sequences when a cytosine nucleotide is followed by a guanine nucleotide (CpG sites).

“There are thousands of CpG sites in our DNA sequence.  We used CpG sites that are highly associated with chronological age to code for the epigenetic age. These CpG sites range from dozens to a few hundreds depending on different methods used to calculate the epigenetic age,” says Xiao, who is first author on the study.

The researchers measure epigenetic age acceleration (EAA) during and after cancer treatment and its association with inflammation and fatigue patients with head and neck cancer.

They calculate EAA using the Levine epigenetic clock (DNAmPhenoAge) based on blood DNA methylation measures using a proprietary Illumina MethylationEPIC BeadChip.  DNAmPhenoAge is a second-generation epigenetic age measure that incorporates methylation data on 513 CpG sites and predicts phenotypic age, lifespan and healthspan, adjusted for chronological age.

The authors also use three other epigenetic methods to predict phenotypic age that consider different sets of CpG islands in the genome to capture different molecular processes of aging.

The 133 patients the researchers focus on—mostly men and White—were at advanced stages of head and neck cancer and received chemoradiation treatment during the study.

“Among cancer patients, those with more fatigue and inflammation may experience accelerated epigenetic age, compared to those with less fatigue and inflammation.  Our study of head and neck cancer patients has found that patients with severe fatigue experienced 3.1 years acceleration in epigenetic age than those with low fatigue…patients with high levels of inflammation exhibited approximately 5 years acceleration in epigenetic age, and inflammation appeared to account for most of the effects of EAA on fatigue,” says Xiao.

The largest increase in EAA of 4.9 years, the authors report, is seen immediately after radiotherapy, mostly in combination with chemotherapy, and the changes remain statistically significant over time.

Through correlation studies, the author show enhanced EAA is associated with elevated fatigue, and patients with severe fatigue experienced 3.1 years higher EAA than those with low fatigue.

The authors consider inflammatory markers linked to cancer-related fatigue in earlier studies. The authors measure these inflammatory at the end of radiotherapy, and a year after radiotherapy.  They take duplicate measures of interleukins IL1ra, IL-1β, IL-6, IL-10, TNF, sTNFR2 using multiplex assays and CRP using the standard turbidimetric assay.

The researchers show EAA is positively associated with inflammatory markers, C-reactive protein (CRP) and interleukin-6 (IL-6), over time. Patients who had high CRP show an EAA increase of 4.6 years while patients who had high IL-6 levels show an EAA increase of 5.9 years.

The authors conclude CRP and IL-6 mediate the association between EAA and fatigue and note, “Inflammation may be a target to reduce the impact of age acceleration on poor functional outcomes… Interventional studies to reduce inflammation might significantly benefit patients who have cancer, in decelerating the aging process and subsequently reducing age-related chronic health problems such as fatigue.”

Notably, this accelerated epigenetic age after cancer treatments can gradually return to the pre-treatment level either naturally over time, or by reducing inflammation.

“Our findings add to the body of evidence suggesting that long-term toxicity and possibly increased mortality incurred from anti-cancer treatments for patients with HNC may be related to increased EAA and its association with inflammation,” says Xiao. “Future studies could examine the vulnerabilities that may account for sustained high EAA, fatigue, and inflammation among patients…The long-term effect of cancer and its treatment on epigenetic age, fatigue, and inflammation still needs more investigations.”

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