Using an Epigenetic Clock to Assess Biological Aging After Cancer Treatment

An epigenetic clock may reveal biological aging after cancer treatment and allow fatigue to be measured objectively.

Within our cell nuclei, long-term storage of genetic information and the instructions needed for continuation of generations and biological development are provided by the complex DNA molecule. DNA instructions are expressed through genes, and all the instructions in DNA together are called the genome.

Genes in the genome are expressed in particular cells at particular times. Epigenetic mechanisms enable this systematic activity. All components involved in epigenetic regulation and mechanisms together are called the epigenome.

Figure explanation: Epigenetics means beyond genetics and studies how genes behave and are regulated. Epigenetic mechanisms do not change DNA or gene structure but determine whether a gene is active: genetic expression changes without mutation. The best-known changes are DNA methylation and histone modification.

Measuring Age with an Epigenetic Clock

Epigenetic clocks measuring DNA methylation status at particular sites across the genome have emerged as reliable estimators of biological age. Certain clocks may predict cancer development risk as well as cancer-related death.

Note: Age is described in two ways: chronological and biological. Chronological age is calendar age; biological age describes the age of our body / cells / organs, or functional status, and is also called real age. Biological age is lower than chronological age in some people and higher in others.

Epigenetic Age Acceleration

Cancer published a new study in which an epigenetic clock showed that, in head and neck cancer patients, treatment was associated with having a DNA methylation age greater than chronological age, termed epigenetic age acceleration.

Epigenetic age acceleration was also linked to increases in inflammatory molecules and patient-reported fatigue. The researchers say these findings suggest that epigenetic clocks may offer an objective approach to assessing and monitoring fatigue.

The lead researcher, Associate Professor Dr. Canhua Xiao of Emory University's School of Nursing in Atlanta, said: “Our study is among the first to investigate the association between epigenetic age acceleration, inflammation and fatigue in cancer patients” .

A Hidden Mechanism Behind Fatigue: DNA Methylation

Researchers have shown that almost all patients with head and neck cancer, after radiotherapy and chemotherapy, experience fatigue that can persist for up to 2 years after treatment.

Dr. Xiao and colleagues had previously observed a strong association between greater fatigue and increased inflammation, but the underlying biological processes and possible role of DNA methylation were unknown.

With this in mind, researchers studied head and neck cancer patients without distant-tissue metastasis: 133 patients, mostly men (72%) and white. Approximately half of the cancers (53%) were associated with HPV infection.

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

Researchers assessed epigenetic age acceleration, fatigue and inflammation at 4 time points: before radiotherapy, immediately after it, 6 months after completion and 12 months after completion.

Epigenetic age acceleration was calculated using the epigenetic clock DNAm PhenoAge. Fatigue was assessed using the Multidimensional Fatigue Inventory (MFI-20) questionnaire, and inflammation through plasma inflammatory marker levels.

The greatest increase in epigenetic age acceleration occurred immediately after radiotherapy, averaging 4.9 years higher than before treatment. There was no significant increase at 6 or 12 months after radiotherapy.

Researchers also found a significant increase in epigenetic age acceleration at treatment completion in patients receiving chemotherapy compared with those not receiving it (4.7 years).

Half of patients reported severe fatigue at some point during the study, particularly immediately after treatment. Their epigenetic age acceleration averaged 3.1 years higher than in patients with low fatigue.

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

Over time, epigenetic age acceleration was 4.6 years higher in patients with high CRP and 5.9 years higher in those with high IL-6, compared with patients with low levels.

Researchers found that CRP, IL-6 and IL-1 receptor antagonist levels explained the observed association between epigenetic age acceleration and fatigue.

Does Epigenetic Aging Cause Fatigue and Other Outcomes?

Dr. Xiao said there was no definitive answer to whether epigenetic aging causes inflammation or fatigue, or vice versa. Researchers found a strong association among epigenetic aging, inflammation and fatigue even before cancer treatment.

Dr. Xiao said: “Whether or not patients were treated, higher epigenetic age acceleration was accompanied by greater inflammation and fatigue”.

What causes accelerated epigenetic aging after cancer treatment is also unclear. One possible scenario proposed by Dr. Xiao and colleagues is: Radiotherapy and chemotherapy cause DNA damage that triggers methylation changes and cellular aging, leading to increased inflammation and consequently more fatigue. In the months after treatment, epigenetic aging then slows and nearly matches chronological age as cells have time to repair DNA damage.

However, Dr. Xiao emphasizes that more research is needed to understand what is actually happening.

Early-stage breast cancer patients in a separate study similarly showed increased epigenetic age acceleration after radiotherapy. Those researchers did not examine its association with fatigue. Dr. Xiao said: “My guess is that accelerated aging is probably associated with many outcomes arising from cancer. We plan to investigate whether treatments such as targeted therapies and immune checkpoint inhibitors are also associated with epigenetic age acceleration.” .

Is Epigenetic Age Acceleration a Cause or a Consequence?

Another question is whether epigenetic age acceleration directly causes cancer and other age-related diseases. Professor William M. Grady of Fred Hutchinson Cancer Research Center, who studies epigenetic age acceleration in cancer patients, notes that a subset has marked acceleration independently of cancer treatment.

Dr. Grady said that detecting epigenetic age acceleration several years before cancer onset suggests a possible causal link. On the other hand, it may merely indicate accumulation of aging cells or other age-related variables causing cancer.

Can Epigenetic Clocks Help Improve Cancer Patient Outcomes?

The current findings identify areas to investigate for preventing or reducing adverse effects of cancer and treatment. Dr. Xiao said: “If we have strategies to slow aging and reduce inflammation, patient outcomes may be better. That is our ultimate goal.“.

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

Dr. Grady said: “Although we would love a drug that could reverse epigenetic aging, such things do not exist”, adding that drugs known to alter DNA methylation do exist but are highly toxic.

University of California professor Sue S. Yom was not involved in the study but wrote an editorial in Cancer: The study's more immediate impact may be suggesting that an established methodology, calculating epigenetic age acceleration using DNAm FenoAge, could provide an objective biological measure of fatigue and other quality-of-life issues in cancer patients.

Dr. Yom said calculating epigenetic age acceleration is unlikely to become part of clinical practice because it is highly sophisticated. It could, however, become an important research tool and improve tools such as the MFI-20 questionnaire for assessing fatigue presence and severity. She added that many cancer studies investigate whether inflammatory markers like those assessed here can biologically measure fatigue and other clinical outcomes. These markers have not been reliable, however, because they vary greatly between normal patients, and levels within an individual may fluctuate substantially due to brief changes such as a mild allergic reaction.

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

“The more biology and physiology we can add to this topic, the more objective it looks and the more funding may become possible.”