Long-term follow-up of survivors of childhood Hodgkin lymphoma from the St. Jude Lifetime Cohort showed signs of “epigenetic accelerated aging,” and many of these survivors had signs of neurocognitive impairment by their late 30s, researchers reported at the 2022 American Society of Hematology (ASH) Annual Meeting and Exposition.¹

The study analyzed epigenetic (ie, biologic) age, which is a marker of changes to gene expression that accrue over a person’s lifetime based on the level of DNA methylation measured in blood samples. They also evaluated cognition via a battery of tests.

“We found that biologic aging is associated with long-term neurocognitive impairment in Hodgkin lymphoma survivors.”

— AnnaLynn M. Williams, PhD, MS

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“We found that biologic aging is associated with long-term neurocognitive impairment in Hodgkin lymphoma survivors,” said AnnaLynn M. Williams, PhD, MS, of the Wilmot Cancer Institute at the University of Rochester School of Medicine and Dentistry in New York. “Specifically, we see strong and consistent associations with memory impairment, which suggests that biologic aging may be likely related to cognitive aging.”

Study Background

The authors previously reported that survivors of childhood and adolescent Hodgkin lymphoma may be more likely to self-report problems with neurocognitive functioning compared with their siblings.² The effects were not associated with previous treatment but were related to chronic comorbidities, according to Dr. Williams.

“This prompted us to think about the risk for long-term impairments in a different way than specifically an early-onset–aging framework,” she continued. “In the current study, our question was whether biologic aging is associated with neurocognitive function in long-term survivors of Hodgkin lymphoma.”

St. Jude Lifetime Cohort

The study involved nearly 500 participants of the St. Jude Lifetime Cohort, which is a population of adults who survived childhood cancers. The subjects, now in their late 30s, included 215 survivors of childhood Hodgkin lymphoma and 282 individuals who had not developed cancer.

The groups were similar in age and gender but were not propensity matched. The cancer survivors had a mean age of 39 and were at least 5 years from their diagnosis (mean, 9 years). Participants submitted blood samples and underwent a series of validated neurocognitive tests to assess attention, processing speed, memory, and executive function.

Genome-wide DNA methylation data were generated from peripheral blood mononuclear cell–derived DNA on the Illumina EPIC 850K assay; the assay evaluates methylation values across 150,000 CpG (cytosine and guanine separated by a phosphate) sites on the genome. Epigenetic age was calculated according to the DNAm PhenoAge assay, developed by Levine et al.³ DNAm PhenoAge is considered a composite biomarker that captures organismal age and the functional state of many organ systems and tissues, above and beyond what is explained by chronologic time.

“We chose this epigenetic ‘clock’ because it is not only trained to predict chronologic age but also multimorbidity and mortality, to get more of that physiologic aging as well,” Dr. Williams said.

Epigenetic age acceleration was defined as the residual from regressing the epigenetic age on chronologic age: Higher acceleration suggests an older biological age relative to the individual’s chronologic age. “Essentially, you can think of this as the difference between someone’s epigenetic age and his or her chronologic age,” she explained.

The analysis compared epigenetic accelerated age in Hodgkin lymphoma survivors and controls. The investigators compared neurocognitive Z-scores in those in the second and third tertiles of age acceleration with those in the first tertile, adjusted for sex, age at diagnosis, and use of high-dose methotrexate. (A negative Z-score means that someone has an overall score that is lower than the average of the entire cohort at baseline.)

Survivors Were Nearly 8 Years Older,
Epigenetically Speaking

Researchers found that the difference between epigenetic age and chronologic age was on average 7.7 years greater among Hodgkin lymphoma survivors compared with the control group. The adjusted epigenetic accelerated age was –3.5 years for controls and +4.2 years for survivors (P < .001). Overall, more than 80% of Hodgkin lymphoma survivors showed evidence of accelerated epigenetic aging compared with 23% in the control group, Dr. Williams reported.

Tests of executive function also showed marked differences. Compared with tertile 1 of epigenetic aging acceleration, survivors in the second and third tertiles performed significantly worse (P < .05) on the task of visual motor processing speed. Similarly, significant deficits in short-term memory (P < .01), verbal learning (P < .05), and long-term verbal recall (P < .05) were shown vs tertile 1.

“All the differences hover around half a standard deviation, which we also consider clinically meaningful,” Dr. Williams said. She noted that the observed degree of impairment may not be readily apparent to friends or family members but is likely noticed by the survivors themselves.

“These types of memory issues are something people tend to notice first with aging-related disorders such as Alzheimer’s and dementia,” explained Dr. Williams. “I hope our study brings awareness to the fact that these underlying biologic changes are not only associated with heart disease and other chronic conditions that we have been aware of in survivors, but also with poor neurocognitive function.”

What Is Causing This?

“Our hypothesis is that treatments such as chest radiation and alkylators are accelerating biologic aging, thus placing patients on a different trajectory for these neurocognitive outcomes. And they are happening sooner than they would have, had the individuals never been treated for cancer in the first place. It’s more of an accumulation of damage,” Dr. Williams added.

Asked in a press briefing whether contemporary treatments could be less impactful on epigenetic aging and cognition, Dr. Williams said that patients still receive intensive therapies. “It could be that the degree of this association may not be as large, but I believe it would still exist,” she responded.

Can We Intervene?

The findings suggest childhood cancer survivors may benefit from additional screening or interventions to mitigate aging-related cognitive declines starting in early adulthood, Dr. Williams continued. “I think we should start with the no-brainers, like physical activity, maybe cognitive behavioral therapy, or some other neurocognitive intervention…. They are probably the next steps for these very high–risk patients,” she said. 

DISCLOSURE: Dr. Williams reported no conflicts of interest.

REFERENCES

1. Williams AM, Dong Q, Phillips NS, et al: Epigenetic age acceleration and neurocognitive function among long-term survivors of pediatric Hodgkin lymphoma: A report from the St. Jude Lifetime Cohort. 2022 ASH Annual Meeting and Exposition. Abstract 902. Presented December 12, 2022.

2. Williams AM, Mirzaei Salehabadi S, Xing M, et al: Modifiable risk factors for neurocognitive and psychosocial problems after Hodgkin lymphoma. Blood 139:3073-3086, 2022.

3. Levine ME, Lu AT, Quach A, et al: An epigenetic biomarker of aging for lifespan and healthspan. Aging (Albany NY) 10:573-591, 2018.