ADULT childhood cancer survivors demonstrated accelerated brain aging that tracked with cranial radiation and poorer neurocognition.
Accelerated Brain Aging Measured by BrainAGE
Long term survivors of childhood cancer may carry a measurable brain age gap decades after treatment, according to a cross-sectional analysis from the St. Jude Lifetime Cohort Study. Investigators compared brain age gap estimation (BrainAGE), defined as estimated brain age minus chronological age, in 253 adult survivors of childhood cancer and 43 community controls with no childhood cancer history. Participants were at least 18 years old and completed whole brain MRI alongside neurocognitive testing.
Survivors had higher mean BrainAGE scores than controls, corresponding to an estimated brain age about 6.6 years older than chronological age compared with 0.7 years in controls (P<.001). The analysis window for BrainAGE spanned January 2016 to February 2021, with statistical analyses completed through March 2025.
Accelerated Brain Aging and Neurocognitive Risk
Higher BrainAGE was consistently linked to worse performance across several neurocognitive domains. After adjustment for age at diagnosis and sex, each 10 year increase in BrainAGE was associated with lower z scores for cognitive flexibility, processing speed, working memory, visual memory, vocabulary, and reading. The largest decrement was seen for cognitive flexibility (β, -0.63), followed by processing speed (β, -0.49).
Biomarkers and Treatment Exposures Track With BrainAGE
The team explored whether plasma biomarkers of oxidative stress, neuroinflammation, and cardiovascular health correlated with older BrainAGE scores and prior central nervous system directed therapy. Neurofilament light was correlated with BrainAGE in female survivors (ρ, 0.24; P=.04). Female survivors diagnosed before age 10 years who received 40 Gy or higher cranial radiation had mean BrainAGE scores more than 30 years older than chronological age.
Sex hormone precursors also appeared relevant in females, with lower levels correlated with higher BrainAGE and with higher cranial radiation dose. Among male survivors, BrainAGE and cranial radiation dose were correlated with malondialdehyde and with oxidized low-density lipoprotein, supporting a link between atherogenicity and accelerated brain aging.
What This Could Mean for Survivorship Care
Together, these findings connect accelerated brain aging to neurocognitive outcomes and to biological signals tied to neuronal injury, vascular risk, and prior cranial radiation exposure. The authors suggest the results can inform future efforts to reduce vascular disease risk and preserve neurocognition in adult survivors of childhood cancer.
Reference: Phillips NS et al. Accelerated Brain Aging, Atherogenicity, and Neurocognition in Adult Survivors of Childhood Cancer. JAMA Netw Open. 2025;8(12):e2551865.
