Does Epigenetic Aging Cause Fatigue and Other Outcomes?

There is no solid answer to the question of whether epigenetic aging actually causes inflammation or fatigue, or vice-versa, Dr Xiao noted. The researchers did find a strong association between epigenetic aging, inflammation, and fatigue even before patients received cancer treatment.

“No matter whether patients receive treatment or not, if they have higher epigenetic age acceleration, they will have higher inflammation and fatigue,” Dr Xiao explained.

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It is also unclear what caused epigenetic aging to speed up after cancer treatment. One possible scenario, which Dr Xiao and colleagues suggested, is that radiation and chemotherapy cause DNA damage that triggers changes in DNA methylation and causes cell senescence, which may lead to increased inflammation and, in turn, greater fatigue. Then, in the months following treatment, epigenetic aging slows down and more or less matches chronological age because cells have had time to repair the DNA damage.

However, Dr Xiao stressed that more investigation is needed to understand what is really going on.

A separate study in patients with early-stage breast cancer similarly found an increase in epigenetic age acceleration after radiation treatment, although investigators involved in that study did not look at the association between epigenetic age acceleration and patient outcomes such as fatigue.5

“My guess is that aging acceleration is probably the link to many things related to cancer outcomes,” Dr Xiao proposed. She is planning to study whether other types of cancer treatments, such as those that involve targeted therapies and immune checkpoint inhibitors, are associated with epigenetic age acceleration.

Another big question is whether epigenetic age acceleration directly contributes to the development of cancer and other age-related diseases.

A subset of cancer patients have marked epigenetic age acceleration regardless of cancer treatment, noted William M. Grady, MD, a professor at Fred Hutchinson Cancer Research Center and medical director of the Gastrointestinal Cancer Prevention Program at Seattle Cancer Care Alliance, who studies epigenetic age acceleration in cancer patients but was not involved in the current study.

On the one hand, the fact that epigenetic age acceleration can be detected in people several years prior to cancer onset suggests a possible causal relationship, Dr Grady said. On the other hand, he added, epigenetic age acceleration may just be a marker for the accumulation of senescent cells or other age-related changes that cause cancer.

Can Epigenetic Clocks Help Improve Outcomes for Cancer Patients?

The findings of the current study hint at areas that may be explored to prevent or reduce the negative effects of cancer and cancer treatment.

“If we have strategies to decelerate the aging and reduce inflammation, patient outcomes may be better. That is the ultimate goal,” Dr Xiao said.

But at least for now, the ability to slow biological aging is far from reality.

“Although we’d love to have a drug that could reverse epigenetic aging, there are no such things,” Dr Grady said. There are drugs that are known to alter DNA methylation, but they are highly toxic, he noted.

The more immediate impact of the study could be that it suggests an established methodology — calculating epigenetic age acceleration using DNAm PhenoAge — may provide an objective, biologic measure of fatigue and other quality-of-life issues for cancer patients, said Sue S. Yom, MD, PhD, a professor at the University of California, San Francisco, who was not involved in the study but wrote an editorial about it in Cancer.4

It is unlikely that calculating epigenetic age acceleration will become a routine part of clinical practice because it is a fairly advanced technique, Dr Yom said. She noted, however, that it could become an important tool in research and improve upon instruments such as the MFI-20 questionnaire for determining the presence and severity of fatigue.

Dr Yom added that many studies in the cancer literature have explored whether the levels of inflammatory markers, such as the ones assessed in the current study, could be biologic measures of fatigue and other clinical outcomes. However, those markers have not been reliable because the normal range varies widely between patients, and levels fluctuate significantly within an individual because of short-term changes, such as a mild allergic reaction.

“I think the epigenetic age acceleration method is probably more stable,” Dr Yom said.

She added that she hopes the availability of a potential new tool to measure fatigue will bring new interest and support to the study of fatigue.

“The more biology and physiology we can bring into it, the more objective it seems, the more funding may be possible,” Dr Yom concluded.

Disclosures: The study was supported by the National Institutes of Health. Some study authors and Dr Yom declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original references for a full list of authors’ disclosures.


  1. Levine ME, Lu AT, Quach A, et al. An epigenetic biomarker of aging for lifespan and healthspan. Aging. 2018;10(4):573-591. doi:10.18632/aging.101414
  2. Durso DF, Bacalini MG, Sala C, et al. Acceleration of leukocytes’ epigenetic age as an early tumor and sex-specific marker of breast and colorectal cancer. Oncotarget. 2017; 8(14):23237–23245. doi:10.18632/oncotarget.15573
  3. Xiao C, Beitler JJ, Peng G, et al. Epigenetic age acceleration, fatigue, and inflammation in patients undergoing radiation therapy for head and neck cancer: A longitudinal study. Cancer. Published online May 24, 2021. doi:10.1002/cncr.33641 
  4. Kober K, Yom SS. Doc, I feel tired… oh really, so how’s your mucositis? Cancer. Published online May 24, 2021. doi:10.1002/cncr.33640
  5. Sehl ME, Carroll JE, Horvath S, Bower JE. The acute effects of adjuvant radiation and chemotherapy on peripheral blood epigenetic age in early stage breast cancer patients. NPJ Breast Cancer. 2020;6:23. doi:10.1038/s41523-020-0161-3