Adolescent, Young Adult Cancer Survivors Experience Accelerated Aging in the Brain

Research findings published in Nature Communications reveal that there may be associations between epigenetic aging and neurocognitive function in long-term survivors of childhood cancer. Specifically, the study authors suggested that epigenetic age acceleration (EAA) was associated with worse attention, processing speed, memory, and executive functions in both central nervous system (CNS)- and non–CNS-treated survivors of cancer.¹

More than 500,000 survivors of childhood cancer live in the US, and over 40% experience persistent neurocognitive impairment years after treatment, explained the authors. These deficits commonly affect attention, memory, executive function, and processing speed, contributing to reduced quality of life, lower educational achievement, and challenges with independent living, social functioning, and employment. Although CNS-directed therapies are known to increase risk for brain abnormalities, emerging evidence suggests that other treatments—such as non-CNS radiation and DNA-damaging chemotherapies—may also significantly impact the CNS. As an example, the authors wrote that long-term survivors of Hodgkin lymphoma who did not receive CNS-directed therapy still demonstrate higher rates of attention and memory impairment and an increased risk of stroke compared with their siblings, both of which are linked to dementia risk.¹

Additionally, non-CNS-directed treatments can cause molecular damage that alters DNA structure, cellular function, signaling, and tissue integrity, particularly when exposures occur during key developmental periods. Over time, accumulated molecular damage may contribute to premature biological aging through inflammation, oxidative stress, immunosenescence, telomere attrition, and epigenetic modifications such as EAA. Childhood cancer survivors show shorter telomere length and increased EAA compared with controls who do not have cancer, and these biomarkers have been associated with cognitive decline in older populations, though they have not been well studied in younger survivors.¹

“Young cancer survivors have many more decades of life to live,” AnnaLynn Williams, PhD, study author and research investigator at the University of Rochester Wilmot Cancer Institute in Rochester, New York, said in the news release. “So, if these accelerated aging changes are occurring early on and setting them on a different trajectory, the goal is to intervene to not only increase their lifespan but improve their quality of life.”²

For this study, a total of 1413 adult survivors of childhood cancer and 282 controls who did not have cancer from the St. Jude Lifetime Cohort (SJLIFE) had available biospecimens and neurocognitive data from the same time point in long-term survivorship and were included in this analysis. On average, survivors were about 26 years from diagnosis and did not differ significantly in age at evaluation from the controls. Analyses were stratified by receipt of CNS-directed therapy during treatment for childhood cancer, because previous research demonstrated this is associated with increased vulnerability to aging-related changes due to diminished cognitive reserve.¹

The CNS-treated group primarily consisted of acute lymphoblastic leukemia survivors (77%), whereas the non–CNS-treated group had high proportions of Hodgkin lymphoma (32%) and Wilms tumor (11%) survivors.

First, the investigators compared survivors in the analytic sample to the remaining survivors in SJLIFE to examine any potential for selection bias. Compared with non–CNS-treated survivors without biomarker data, those with biomarker data were more likely to have received non–CNS-directed radiation. Similarly, CNS-treated survivors with biomarker data were less likely to have had CNS-directed radiation and high-dose cytarabine compared with those without biomarker data.¹

Overall, the findings suggested that epigenetic aging and neurocognitive aging may be closely linked and that EAA—specifically defined from PCGrimAge or DunedinPACE—may help identify those at greatest risk for neurocognitive impairment and who would benefit most from intervention. Additionally, given the modifiable nature of these biomarkers, they may hold usefulness in detecting preclinical changes in biological aging in response to interventions that are designed to improve both physiologic and cognitive aging trajectories (eg, diet, physical activity, and senolytics).¹

When examining either PCPhenoAge or DunedinPACE, 2 distinct patterns emerged in the CNS-treated and non–CNS-treated groups: the CNS-treated group experienced deficits in memory associated with EAA, whereas the non–CNS group did not. The authors hypothesized that this may be due to the initial neurotoxic effect of therapy in CNS-treated patients being more vulnerable to the effects of continued epigenetic aging on their memory-specific cognitive reserve. Further, the investigators also noted associations between EAA and memory span in the Hodgkin lymphoma subgroup, who are treated without CNS-directed therapy.¹

The authors urged that future longitudinal and mechanistic research will be necessary in both CNS-treated and Hodgkin lymphoma survivors to better understand the potential for a causal relationship between EAA and memory decline. This is critical because these populations are vulnerable to many aging-related late effects that would increase their risk for continued neurocognitive decline which ultimately may manifest as dementia or other cognitive impairment disorders.¹

“It’s kind of like a perfect storm,” Williams concluded. “This is why we see many survivors having worse educational and employment outcomes than their siblings.”²

REFERENCES

1. Williams AM, Phillips NS, Dong Q, et al. Epigenetic age acceleration, telomere length, and neurocognitive function in long-term survivors of childhood cancer. Nat Commun 16, 10655 (2025). doi:10.1038/s41467-025-65664-5

2. University of Rochester Medical Center. Researchers raise concerns about faster aging, possible early-onset dementia, for children and young adult cancer survivors. News release. January 7, 2026. Accessed February 4, 2026. https://www.eurekalert.org/news-releases/1111871